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Cardiac Amyloidosis
General Medicine for Palliative Physicians Conference 2020
Dr Eleanor Wicks
Clinical Lead of Inherited Cardiac Diseases Service
Consultant Cardiologist and Honorary Senior Clinical Lecture in Heart Failure, Imaging, Inherited and Acquired
Cardiac Diseases
Oxford University Hospitals
@eleanorwicks @HeartFailureOUH @OxfordICC @Cardiomyopathy
Disclosures
• Consultancy and speaker fees
• Novartis, Servier, Alnylam
• Advisory services
• James Lind Alliance Project Steering Partnership
• Cardiomyopathy UK, BHF, Takeda
• Membership and advisory committees
• ESC myocardial and pericardial diseases working group
• Association for Inherited Cardiac Conditions
• Cardiomyopathy UK and BHF Charity involvement
• Inherited cardiac conditions (ICC) curriculum and training working group
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Amyloidosis
• Aims:
– Improve awareness and update your knowledge &
understanding of amyloidosis
– Reinforce knowledge of epidemiology, red flags and
challenges in the diagnosis, assessment (and staging) of
cardiac amyloidosis
– Overview new treatment options
– Think about a coordinated, multi-disciplinary approach
Case 1
6MWT, 6-minute walk test; BJP, Bence Jones protein; CMR, cardiac magnetic resonance imaging; eGFR, estimated glomerular filtration rate; FLC, free light chain; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SAP, serum amyloid P; TnT, troponin T; UPT, urine preservative transport
• 46-year old lady presented with nephrotic syndrome in January 2017• Renal biopsy – minimal change disease• Treated with prednisolone – no response• Cyclosporine A added – no response• June 2017, repeat renal biopsy – amyloid• Cr 143, eGFR 35ml/min, serum albumin 17g/L, 24hr UPT 13.2 g• NT-proBNP 465 ng/L, TnT 38 ng/L• κ FLC 72.5, λ FLC 172.4, κ/λ ratio 0.42, lambda BJP 0.4 g/24hr• Bone marrow biopsy – 7% lambda restricted plasma cells• Echocardiogram – no definite evidence of amyloid• Non-contrast CMR – likely early cardiac amyloid• SAP scan – moderate visceral amyloid load in the spleen and kidneys• 6MWT – 438 metres (82% of normal for age)
Kidney damage with proteinuria, low albumin, hyperlipidaemia, +++ oedemaComplications: blood clots, HTN, infections
Kidney damage with proteinuria, low albumin, hyperlipidaemia, +++ oedemaComplications: blood clots, HTN, infections
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Case 1
• Both renal biopsies stained
– AL (lambda sub-type) amyloid in both samples (by IHC)
Diagnosis: Systemic AL amyloidosis
Mayo Stage II disease1
• Treated with CVD to clonal complete response (CR)
• Progression to ESRD, commenced HD in February 2018
• Listed for kidney transplant
AL, amyloidosis light chain; CVD, cyclophosphamide, Velcade® and dexamethasone; ESRD, end-stage renal disease; HD, hemodialysis; IHC, immunohistochemistry
Dispenzieri A, et al. J Clin Oncol 2004;22(18):3751–3757
Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 monthsStage 2: one or other marker high survival 10.5 monthsStage 3: both markers high survival 3.5 months
Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 monthsStage 2: one or other marker high survival 10.5 monthsStage 3: both markers high survival 3.5 months
Case 2
• 77-year-old male
• Admitted with congestive cardiac failure
• Bilateral carpal tunnel decompressions 15 years ago
• Hx of AF and longstanding HTN
• No FH of note
• CKD (creatinine 180), proteinuria ++
• Resistant to diuretics +++
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CXR
ECG
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CMR
DPD Scintigraphy: Perugini stage
Perugini et al, JACC 2005
Huff et al, EHJ 2014
Grade 2 – cardiac uptake with intensity similar or greater than bone signal
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Diagnostic workup
Clinical Suspicion(Hx, ECG, echo +/- CMR)
DPD scan + serum, urine IFE + FLCs
+ve DPD, -ve screen +ve DPD, +ve screen
TTR cardiac amyloid likely
1. Offload2. Refer ICC clinic/NAC3. Discharge
AL amyloid possible
1. Offload 2. Liaise NAC and Haem as IP3. Consider endomyocardial biopsy4. Look for other organ involvement
-ve DPD, +ve screen -ve DPD, -ve screen
Consider alternative diagnosis
Treatment
• Diuretics as needed -> offload acutely
• Long term usual fluid balance advice
• Little role for ACEi, ARBs, BBs, rate limiting CCBs
• Digoxin controversial – generally avoid
Novel therapies considered:
• Transthyretin tetramer stabilising agents (diflusinal and tafamidis)
• Antisense and interfering RNA therapeutics (reduce TTR
production by 80-90%)
• Monoclonal anti-SAP antibodies (clearance of established amyloid)
Maurer et al, Circ Heart Fail 2015; Sekijima et al, Society of Amyloidosis 2006; Coelho et al, NEJM 2013; Ackermann et al, the International Society of Amyloidosis 2012; Richards et al, NEJM 2015.
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Case 3
• 68-year old lady, previously fit and well
• Gradual worsening of SOB
• She had several investigations, including an ECG and echo → significant LVH and voltage criteria for LVH on ECG
• Aortic stenosis and was planned for aortic valve surgery
• Before surgery she was scheduled for a CMR scan – she had pulmonary oedema during cardiac MRI → scan interrupted before LGE
• Emergency surgery and had mechanical aortic valve replacement
• Struggled thereafter with SOB
Case 3
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Echo 5 years later
Features of HCM: In an adult, HCM is defined by a wall thickness ≥15 mm in one or more LV myocardial segments – as measured by any imaging technique (echo, CMR or CT), that is not explained solely by loading conditions
CMR 5 years later
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CMR 5 years later: typical features of amyloid
Classic extensive ‘zebra’ scar pattern on late enhancement
Suspected cardiac amyloidosis -> Immunofixation serum and urine FL and electrophoresis-> negative
DPD
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Confirming ATTR amyloidosis
AApoA1, apolipoprotein A-I; AL, amyloidosis light chain; ATTR, TTR amyloidosis; CMR, cardiac magnetic resonance imaging;DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; HDMP, hydroxymethylenediphosphonate; PYP, pyrophosphate; TTR, transthyretinGillmore JD, et al. Circulation 2016;133(24):2404–2412
Amyloid in AS
• Present in up to 15% of patients with AS and up to 30% of low-flow, low gradient AS
• In AS, CA is associated with increased risk of HF, mortality, treatment futility with AVR
• Look for specific red flags and confirm the diagnosis
• Transcatheter rather than surgical AVR preferred
• Start treatment for TTR amyloid as soon as diagnosis confirmed
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CHAD-STOP mnemonic for initial steps in CA:C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker)H: high heart rate maintenance A: anticoagulationD: diureticsSTOP: STOP betablockers and calcium channel blockers (to optimize HR, CO and preload), STOP digoxin and STOP renin-angiotensin-aldosterone inhibitors (to minimize severe hypotension, esp in autonomic dysfunction)
CHAD-STOP mnemonic for initial steps in CA:C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker)H: high heart rate maintenance A: anticoagulationD: diureticsSTOP: STOP betablockers and calcium channel blockers (to optimize HR, CO and preload), STOP digoxin and STOP renin-angiotensin-aldosterone inhibitors (to minimize severe hypotension, esp in autonomic dysfunction)
WHAT IS AMYLOIDOSIS?
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Amyloidosis
• Extracellular deposition of abnormally folded protein
• Over 30 different proteins
• Accumulate in tissues as amyloid fibrils which leads to progressive dysfunction
Bind Congo red and SAP
Unusual stability
Damage tissue structure
and organ function Serum Amyloid P (SAP) scintigraphy
Types of amyloidosis (differential diagnoses)
• Cardiac AL (light chain) amyloidosis
• Cardiac transthyretin (ATTR) amyloidosis
– Wild-type ATTR (Senile Systemic/Senile Cardiac)
– Hereditary transthyretin amyloidosis (hATTR) mutation of TTR gene e.g. V122I, T60A
• AA amyloidosis
• Rare (genetic)
• Apo A1/A2
• Lysozyme
Gonzalez-Lopez E, et al. Eur Heart J 2015;36:2585-94
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Amyloid fibril proteins
Amyloid fibril protein (circulating)
• Light chain of immunoglobulin
• Amyloid A protein
• ‘Normal’ TTR
• ‘Mutated’ TTR
There are more than 30 known amyloid fibril proteins!
Amyloid type
• AL
• AA
• ATTRwt
• hATTR
AA, amyloid A amyloidosis; AL, amyloidosis light chain; hATTR, hereditary; TTR amyloidosis; TTR, transthyretin; wt, wild-type. Data courtesy of National Amyloidosis Centre data 2018 (unpublished)
Terminology and classification
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Key facts 1: Cardiac Amyloidosis
• Rare form of cardiomyopathy, challenging to diagnose, often associated with poor prognosis
• Amyloidosis = a collection of disorders of protein mis-folding
• Mis-folded protein forms aggregates within a cell which are potentially toxic
• Excess of protein or impairment of clearance of abnormal protein can lead to amyloidosis
Knowles TP, et al. Nat Rev Mol Cell Biol. 2014;15:384–96.
Key facts 2
• Two types account for 95% of all cardiac amyloidosis:
• AL (light chain) fibril deposits
– Clonal plasma cell dyscrasia (disorder) that results in overproduction and misfolding of light chain antibody fragments
• TTR (transthyretin) deposits
– Due to misfolding of the liver-derived precursor protein transthyretin (TTR, previously called prealbumin)
AL, light chain; TTR, transthyretin. Donnelly J, Hanna M. Cleve Clin J Med 2017;84(12 Suppl 3):12–26.
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CARDIAC AL AMYLOIDOSIS
Cardiac AL amyloidosis
• Commonest diagnosed form of cardiac amyloidosis
• Cardiac involvement in 50-90% of systemic AL amyloidosis, often HF
• Derived from monoclonal immunoglobulin light chain
• Poor prognosis - median survival 12 months
• Median age at diagnosis is 50-60yrs
• May co-exist with multiple myeloma (10-15%) or any B-cell dyscrasia
but >80% due to subtle or ‘benign’ gammopathies
• Full clinical evaluation and investigations (ECG, Echo, CMR, biomarkers,
biopsy, SAP ± DPD scan, immunofixation of urine and serum, serum
immunoglobulin FLC, urine electrophoresis, bone marrow biopsy
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Cardiac AL amyloidosis: management
Manage cardiac disease:
– Diuresis, anticoagulate in AF (thromboembolism)
– BB, vasoactive drugs poorly tolerated – hypotension
– Avoid digoxin + CCBs as bind amyloid -> toxicity
– PPM but avoid ICDs – SCD common
Treat underlying disease:
• Stop production of paraprotein responsible for AL amyloid
• Oral chemotherapy:
– Melphalan + prednisolone
– High dose chemo with CVD (cyclophosphamide, Velcade® and dexamethasone; or Velcade, methylprednisolone, thalidomide
– ± peripheral autologous stem cell rescue
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CARDIAC ATTR AMYLOIDOSIS
New diagnoses of ATTR amyloidosis in UK
hATTR, hereditary TTR amyloidosis; CMR, cardiac magnetic resonance imaging; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; TTR, transthyretin; wt, wild-type. National Amyloidosis Centre data (unpublished)
Rowczenio D, et al. Orphanet J Rare Dis 2017;12(Suppl 1):165; Lane T, et al. Circulation 2019;140(1):16–26;
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Diagnostic delay in ATTR-CM
35%
23%
42%
CATEGORY 1
Time from 1st Symptom to diagnosis of ATTR-CM
0-6 months 6 months-4 yrs >4 years
ER IP OP ER IP OP ER IP OP0
20
40
60
80
1001 attendance
2 attendances
3 attendances
Year -3 Year -2 Year -1
Percen
tag
e o
f p
atie
nts
Median 17 hospital attendances prior to diagnosis!Median 3 hospital IP episodes prior to diagnosis
Lane, T et al. Circulation 2019;139
ATTR amyloidosis
• Cardiac transthyretin (ATTR) amyloidosis
– Wild-type ATTR (Senile Systemic/Senile Cardiac) (acquired)
– Hereditary transthyretin amyloidosis (hATTR) mutation of TTR gene e.g. V122I, T60A (inherited)
• Wild-type ATTR amyloidosis:
– Predominant cardiomyopathy and presents with symptoms of heart failure, arrhythmias, syncope, AS
– Risk factors for ATTRwt: Predominantly male (95%), increasing age, ?being historically fit
– 40-50% previous CTS, 50% atrial fibrillation at presentation
– Median survival >3 years(h)ATTR-CM, (hereditary) TTR amyloidosis cardiomyopathy; HF, heart failure; TTR, transthyretin; wt, wild-typeGertz MA, et al. J Am Coll Cardiol 2015;66(21):2451–2466; Conceição et al, J Peripher Nerv Syst 2016;21(1):5–9; Tanskanen M, et al. Ann Med 2008;40(3):232–239; Grogan M, et al. J Am Coll Cardiol 2016;68(10):1014–20; Pinney JH, et al. J Am Heart Assoc 2013;2(2):e000098
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Wild type transthyretin (ATTR) Amyloidosis
• Autopsy studies indicate cardiac ATTR amyloid deposits are present in up to 25% of men over 80 years of age
• 13% of hospitalised patients with HFpEF (and +++ more with AS ?32%) have been shown to have amyloidosis…for which there are now disease specific treatments
– but majority not diagnosed with amyloidosis in life
– Misdiagnosis - poor sensitivity and specificity of echocardiography
– Deposits clinically significant?
CTS: carpel tunnel syndrome
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Key facts 3: Modern epidemiology of ATTR amyloidosis
Frequency of cardiac ATTR amyloidosis deposits in different settings
• Amyloid deposits in autopsied subjects (mean age 69 years) without HF 16%
• Unexpected bone tracer myocardial uptake in patients >75 years undergoing 2.7%
scintigraphy for non-cardiac reasons 2
• Unexpected TTR mutations in patients with supposed sarcomeric HCM 3 5%
• Hospitalised patients with HFpEF 4 13%
• Amyloid deposits in autopsied elderly patients (mean age 76 years) with HFpEF 1 16%
• Elderly patients with severe degenerative aortic stenosis 5 32%
HCM: hypertrophic cardiomyopathy; HF: heart failure; HFpEF: heart failure with a preserved ejection fraction.1 Mohammed SF, et al. JACC Heart Fail 2014;2:113-22; 2 Longhi et al. JACC Cardiovasc Imaging 2014;7:531-23 Damy T et al. Eur Heart J 2016;37:1826-34; 4 Gonzalez-Lopez E, et al. Eur Heart J 2015;36:2585-94;5 Castano A, et al. Eur Heart J 2017;38:2879-87; 6 Grogan M, et al. J Am Coll Cardiol 2016;68:1014-20.
Hereditary ATTR amyloidosis
• Amyloid fibril protein is variant transthyretin (TTR)
• Spectrum of hereditary ATTR amyloidosis:– More than 130 genetic amyloidogenic variants of TTR– Autosomal dominant inheritance– Variable penetrance and phenotype, including:
• peripheral & autonomic neuropathy• amyloid cardiomyopathy • vitreous amyloid deposits• leptomeningeal disease
Several single amino acid substitutions associated:• V30M-associated ATTR amyloidosis most prevalent worldwide (Portugal, Sweden,
Japan)• T60A-associated ATTR amyloidosis most prevalent in British and Irish Caucasians • V122I TTR variant present in ~4% of African-Americans
ATTR, TTR amyloidosis; TTR, transthyretin. Reilly MM, et al. J Neurol Neurosurg Psychiatry 1995;59(1):45–49; Carr AS, et al. J Neurol Neurosurg Psychiatry 2016;87(6):620–627
47%
14%
5%
6%
6%
22% T60A
V30M
G47V
V122I
E89K
Other
46 TTR mutations in the UK70.5% T60A CTS (-7.5, 13-0)
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TTR mutations
TTR, transthyretin
• TTR is a single polypeptide chain of 127 amino acids encoded by single gene on chromosome 18 with 4 exons, inherited as AD trait with variable penetrance
• TTR is a tetrameric plasma transport protein for thyroid hormone and retinol-binding protein/vitamin A synthesized in the liver
• Most TTR mutations are single nucleotide substitutions
Genotypic-phenotypic correlation in ATTR amyloidosis
Most prevalent variants in UK:2
T60A: 30%V122I: 64%
V30M and V122I: most
common mutations
worldwide1
Figure adapted from Rapezzi C. et al. Eur Heart J 2013;34:520–8 by permission of Oxford University Press1. Ando Y, et al. Orphanet J Rare Dis 2013;8:31; 2. Lane T, et al. Orphanet J Rare Dis 2015;10(Suppl 1):O26
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Key facts 4: TTR Thr60Ala amyloidosis
• Most common in UK and Ireland
• Later onset (average 61)
• Autonomic involvement early
• Cardiac involvement common
• No vitreous deposits
• Reduced penetrance (related to late onset)
Key facts 5: Transthyretin V122i: AD cause in elderly African Americans
Buxbaum JN, et al. Genet Med 2017; 19: 933:742.
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Prognosis of cardiac amyloidosis
0 12 24 36 48 600
20
40
60
80
100ATTRwt
ATTR T60A
ATTR V122IAL
Time (months)
Perc
en
t su
rviv
al
Median survival in cardiac AL ~12 monthsMedian survival in cardiac ATTR >3 years P<0.001
DIAGNOSIS OF CARDIAC AMYLOIDOSIS
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A form of Restrictive Cardiomyopathy
Restrictive Cardiomyopathy
Primary Restrictive Cardiomyopathy
Secondary Restrictive Cardiomyopathy
Endomyocardial Fibrosis
Loeffler’s Cardiomyopathy
Idiopathic Restrictive Cardiomyopathy
Infiltrative Disease Storage Disease
Amyloidosis
Sarcoidosis
Postirradiation Therapy
Hemochromatosis
Glycogen Storage Disease
Fabry’s Disease
Leung DY & Klein AL. In: Topol EJ, Califf RM, Isner JM, et al, eds. Textbook of
Cardiovascular Medicine. Lippincott-Raven Publishers 1998, pp 604
Amyloid infiltration
Neurological involvement
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Clinical approach
1. Confirm the diagnosis - unusual types and ‘mimics’
2. Symptoms- how bad are these and what is their cause
3. Risk to length of life- SCD high, medium, low
- Disease specific risk assessment- Heart rhythm abnormalities, stroke risk & heart failure risk
- Extent of organ involvement
4. Implications for patient and their family
5. Inheritance and Genetics
Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
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Diagnostic algorithm
AApoA1, apolipoprotein A-I; AL, amyloidosis light chain; ATTR, TTR amyloidosis; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; HDMP, hydroxymethylene diphosphonate; PYP, pyrophosphate; TTR, transthyretin. Gillmore JD, et al. Circulation 2016;133(24):2404–2412
Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
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Diagnosis
• Clinical history
– Symptoms…carpel tunnel!
– Other medical conditions
– Medications - any side effects?
• Family history
• Physical examination
RCM symptoms
Maybe none or only minor symptoms which may progress:
• Breathlessness• Fatigue • Inability to exercise• Chest pain or pressure• Swelling of legs, feet or tummy bloating• Weight loss or gain if fluid +++• Waking at night feeling breathless or needing more pillows to sleep• Palpitations or irregular heart beat• Dizzy spells or fainting…pacemaker• Nausea, poor appetite• Numbness/tingling or carpel tunnel syndrome• …
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Key facts 6: Clinical manifestations of amyloidosis
*Very suggestive of AL amyloidosisAL, amyloidosis light chain; CNS, central nervous system; GI, gastrointestinal; UTI, urinary tract infectionBased on Conceição et al. J Peripher Nerv Syst 2016;21(1):5–9
Myopathy
*Macroglossia
GI manifestations
• *Organomegaly
• Nausea and vomiting
• Changes in GI motility
(i.e. diarrhoea, constipation,
gastroparesis, early satiety)
• Unintentional weight loss
CNS manifestations
• Progressive dementia
• Headache
• Ataxia
• Seizures
• Spastic paresis
• Stroke-like episodes
Renal manifestations
• Proteinuria
• Renal failure
Connective tissue
• Carpal tunnel syndrome
• Spinal Stenosis
Ocular manifestations
• Vitreous opacification
• *Periorbital ecchymosis• Glaucoma
• Abnormal conjunctival vessels
• Papillary abnormalities
Cardiovascular manifestations
• Conduction blocks
• Cardiomyopathy
• Palpitations and arrhythmia
• Mild regurgitation
• Shortness of breath
• Oedema
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
Key facts 6: Diagnostic red flags
• Clinical suspicion
• Neuropathy
• Autonomic dysfunction (in absence of diabetes)
• Cardiac features (pacemaker)
• Irish/Portuguese
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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
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ECG: What to look for
• QRS meeting the voltage criteria
• Low QRS voltage1,2
• Pseudo-infarction patterns of Q wave1
• Conduction abnormalities, including bundle branch block1,2
• Rhythm disturbances (e.g. atrial fibrillation)1,2
Common findings in ECG traces from patients
with Val122Ile hATTR amyloidosis1
Atrial fibrillation, anterolateral
and inferior infarcts (pseudo-
infarcts)
Sinus bradycardia with
first-degree atrioventricular
block, low QRS voltage
and poor precordial
R-wave progression
Sinus rhythm with marked first-
degree atrioventricular block,
low QRS voltage and left bundle
branch block
Marked sinus bradycardia,
inferior infarct
(pseudo-infarct)
ECG, electrocardiogram; hATTR, hereditary TTR amyloidosis; TTR, transthyretinFigure reproduced with permission from Dharmarajan K, Maurer MS. J Am Geriatr Soc 2012;60(4):765–7741. Dharmarajan K, Maurer MS. J Am Geriatr Soc 2012;60(4):765–774; 2. Mohty D, et al. Arch Cardiovasc Dis 2013;106(10):528–540
Typical ECG with low voltage QRS
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Typical ECG in TTR amyloidosis – taller voltages
Risk: atrial fibrillation
• Use of the CHA2DS2-VASc score to calculate stroke risk is
NOT recommended in HCM but what about RCM?
• In general, lifelong therapy with oral anticoagulants is
recommended if any hint of AF or significantly dilated
atria
• If in doubt, anticoagulate
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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
Echocardiogram: Structure
Abnormalities characteristically found in patients with hATTR amyloidosis1,2
• Biventricular thickening, concentric or interventricular septum thickness >12 mm and increased LV mass
• Increase in RV wall thickness
• Increased echogenicity of myocardium with speckled appearance of myocardium (low sensitivity)
• Pleural and pericardial effusions (AL>ATTR)
• Small left ventricular chamber volume
• Bi-atrial enlargement
• Thickening of valve leaflets or intra-atrial septum
Parasternal long axis Parasternal short axis
Restrictive transmitral
Doppler pattern
Tissue Doppler: reduced
longitudinal systolic shortening
and diastolic dysfunctiona
aReduced S’ and E’ velocities, respectivelyAL, amyloidosis light chain; ATTR, TTR amyloidosis; RV, right ventricular; TTR, transthyretin
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Doppler analysis RCM-diagnosis
Impaired ventricular filling
Increased E/A ratio 2
Decreased DT 150 msec
Decreased IVRT 70 msec
Preload?
E
A
Echocardiogram: Myocardial strain imaging
Normal strain pattern Typical strain pattern in cardiac amyloidosis “bull’s eye”
Impaired global strain with relative sparing of the apical region compared with the base of the heart
In patients with aortic stenosis often not present
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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
Additional basic investigations
• To derive type of amyloid
• To assess risk from amyloid
• To assess symptom limitation
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Cardiac biomarkers ATTR: NT-proBNP
A raised NT-proBNP and TnT or TnI are predictive of adversity
Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 monthsStage 2: one or other marker high survival 10.5 monthsStage 3: both markers high survival 3.5 months
Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 monthsStage 2: one or other marker high survival 10.5 monthsStage 3: both markers high survival 3.5 months
Diagnosis – CMR, ETT, Holter
Exercise ECG MRI scan
Holter monitor
CPET
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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
CMR: What to look for
• LGE imaging is used to identify amyloid infiltration directly1
Transmural LGESubendocardial LGENo LGE
CMR, cardiac magnetic resonance imaging; LGE, late gadolinium enhancementFigure reproduced with permission from Fontana M, et al. Circulation 2015;132(16):1570–15791. Fontana M, et al. Circulation 2015;132(16):1570–1579
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Native T1 (mapping) in amyloidosis
AL, amyloidosis light chain; ATTR, TTR amyloidosis; LGE, late gadolinium enhancement; TTR, transthyretinFontana M, et al. JACC Cardiovasc Imaging 2014;7(2):157–165
Native T1 in the hypertrophic phenotype
HCM, hypertrophic cardiomyopathySado DM, et al. Circ Cardiovasc Imaging 2013;6(3):392–398
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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
DPD scintigraphy: 99mTc-DPD uptake in cardiac ATTR amyloidosis1,2
• Grade 1 = Mild cardiac uptake, no attenuation of bone uptake
• Grade 2 = Moderate cardiac uptake greater than bone
• Grade 3 = Strong cardiac uptake with little or no bone signal
Cardiac ATTR amyloidosisPositive - >99% sensitiveGrade 2/3 – 90% specific
Cardiac Bone
99mTc-DPD, technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid; ATTR, TTR amyloidosis; TTR, transthyretin1. Rapezzi C, et al. JACC Cardiovasc Imaging 2011;4(6):659–670; 2. Hutt DF, et al. Eur Heart J Cardiovasc Imaging 2014;15(11):1289–1298
Grade 0 Grade 1 Grade 2 Grade 3
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Cardiac uptake on DPD only ATTR amyloidosis Cardiac uptake on DPD only ATTR amyloidosis
Cardiac uptake on DPD Amyloidosis Cardiac uptake on DPD Amyloidosis
No Cardiac uptake on DPD No amyloidosis No Cardiac uptake on DPD No amyloidosis
Clinical case
• 75-year old gentleman with SOB, echo showed asymmetric increase in LV mass (septum) no MGUS
No plasma cell dyscrasia (negative serum and urine immunofixation, negative FLC)
FLC, free light chain; LV, left ventricular; MGUS, monoclonal gammopathy of unknown significance; SOB, shortness of breath
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Diagnostic algorithm
AApoA1, apolipoprotein A-I; AL, amyloidosis light chain; ATTR, TTR amyloidosis; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; HDMP, hydroxymethylene diphosphonate; PYP, pyrophosphate; TTR, transthyretin. Gillmore JD, et al. Circulation 2016;133(24):2404–2412
Clinical case
• 70-year old gentleman with SOB and oedema, echo showed increase in LV mass (septum)
LV, left ventricular; MGUS, monoclonal gammopathy of unknown significance; SOB, shortness of breath
MGUS
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Diagnostic algorithm
AApoA1, apolipoprotein A-I; AL, amyloidosis light chain; ATTR, TTR amyloidosis; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; HDMP, hydroxymethylene diphosphonate; PYP, pyrophosphate; TTR, transthyretin
Gillmore JD, et al. Circulation 2016;133(24):2404–2412
Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
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SAP scintigraphy following OLT in FAPcan monitor regression of visceral amyloid
FAP, familial amyloid polyneuropathy; OLT, orthotopic liver transplantation; SAP, serum amyloid P
Before OLT +15 months +36 months
Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
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Biopsy
• DPD scintigraphy has a >99% sensitivity for cardiac TTR amyloid, but only 68% specificity
• Rectal, fat, salivary gland biopsies positive in 80% AL, but only in 25% of TTR
• Endomyocardial biopsy currently considered the gold standard of diagnosis
Maleszewski
JJ. Cardiovasc
Pathol 2015;2
4:343‒50.
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Courtesy of Prof. Claudio Rapezzi, Bologna, Italy.
Invasive diagnosis: biopsy
• Amyloid ‘traditionally’ a histological diagnosis via Congo red
staining and demonstration of green birefringence
• Biopsy of affected organ, but
– Heart biopsy - has risk, expense, and requires expertise;
not routinely performed by cardiologists to investigate HF
– Nerve biopsy – not routinely performed by neurologists
• Screening biopsy
– Rectal: invasive, not sensitive
– Abdominal fat aspirate: Simple procedure but highly
variable sensitivityGillmore et al, Circulation 2016. van Gameren II, et al. Arthritis Rheum 2006;54(6):2015–2021; Ansari-Lari MA,
Ali SZ. Diagn Cytopathol 2004;30(3):178–181; Quarta CC, et al. Eur Heart J 2017;38(24):1905–1908
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Key point: Congo red staining
Congo red stain goes off – i.e., needs to be fresh
Slides need to be looked at on microscope with polarizing filters (EQA: 20% UK Pathology Depts
did not have a polarising microscope!!)
UK NEQAS (EQA) audit: 13% assessors failed to demonstrate amyloid
Puchtler staining method recommended
EQA, external quality assessment. Sayed RH, et al. Nephrol Dial Transplant 2014;29(11):2120–2126; Puchtler H, et al. J Histochem Cytochem 1962;10(3):355–364
Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis
Constellation of clinical, laboratory and imaging findings
• History and examination
• Electrocardiogram (ECG)
• Echocardiography (TTE)
• Blood tests: including serum immunofixation, serum free light chains, eGFR, albumin, TnT and NT-proBNP
• Urine tests, including urine immunofixation, 24-hour albuminuria, uPCR and uACR
• Holter monitor for 24-48 hours
• Exercise test or cardiopulmonary exercise test (CPET) ± 6MWT
• Cardiac MRI scan
• DPD scintigraphy (bone scan) (cardiac involvement) ± SAP scan (multi-organ involvement)
• Cardiac catheterization (a right/left heart catheter)
• Endomyocardial biopsy (EMB), staining and proteomic analysis of any available biopsy tissue
• Genetic sequencing
• QoL questionnaire
• Bioimpedance
• Neurophysiology, small-fibre studies, nerve biopsy, skin biopsies, neurofilament light tests
6MWT, 6-minute walk test; DPD, diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiography; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NT-proBNP, N-terminal pro brain-type natriuretic peptide;
QoL, quality of life; SAP, serum amyloid P; TnT, troponin T; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio
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TREATMENT OF CARDIAC AMYLOIDOSIS
General Treatments
• Treat underlying cause (if identified)• Diuretics as needed -> offload acutely• Long term usual fluid balance advice, daily weights• Little role for ACEi, ARBs, BBs, rate limiting CCBs• Digoxin controversial• Rhythm control - Amiodarone• Anticoagulation• Autonomic neyropathy therefore tend to avoid ACEi or
beta-blockers unless already taking them and asymptomatic
• Advanced HF therapies • ?Disease-modifying meds
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Treatments
• Treat underlying cause (if identified)• Diuretics as needed -> offload acutely• Long term usual fluid balance advice• Little role for ACEi, ARBs, BBs, rate limiting CCBs• Digoxin controversial• Rhythm control
– Amiodarone• ?Disease-modifying meds unproven• Anticoagulation• Autonomic neyropathy therefore tend to avoid ACEi or beta-
blockers unless already taking them and asymptomatic • Advanced HF therapies
CHAD-STOP mnemonic for initial steps in CA:C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker)H: high heart rate maintenance A: anticoagulationD: diureticsSTOP: STOP betablockers and calcium channel blockers (to optimize HR, CO and preload), STOP digoxin and STOP renin-angiotensin-aldosterone inhibitors (to minimize severe hypotension, esp in autonomic dysfunction – unless already taking them and they are asymptomatic)
CHAD-STOP mnemonic for initial steps in CA:C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker)H: high heart rate maintenance A: anticoagulationD: diureticsSTOP: STOP betablockers and calcium channel blockers (to optimize HR, CO and preload), STOP digoxin and STOP renin-angiotensin-aldosterone inhibitors (to minimize severe hypotension, esp in autonomic dysfunction – unless already taking them and they are asymptomatic)
Minimise and manage side effects
• Low blood pressure
• Urinary frequency
• Fatigue
• Dizzy spells + fainting on exertion
• Erectile dysfunction
• Orthostatic hypotension, esp with autonomic neuropathy
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Treatment strategies in (ATTR) amyloidosis
Precursor proteinPrecursor protein AmyloidAmyloid
Therapeutic strategies in amyloidosis
Enhance removal of
existing amyloid
▪ Immunotherapy
▪ SAP depletion
Reduce supply of
amyloid
precursor
protein
Stabilise amyloid-
forming proteins
▪ β sheet breakers
Fibril formationFibril formation
Reversion to normally folded protein
Tetramer stabilisers: TafamidisDiflunisalAG10
Liver transplantationGene silencing:• Antisense
oligonucleotides*• Small interfering RNA
PatisiranInotersen
Amyloid deposit clearance• Antibodies• Doxycyline/
TUDCA
SAP, serum amyloid P
Gene silencing:• Small interfering RNA
Tetramer stabiliser
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Treatment strategies in (ATTR) amyloidosis
Precursor proteinPrecursor protein AmyloidAmyloid
Therapeutic strategies in amyloidosis
Enhance removal of
existing amyloid
▪ Immunotherapy
▪ SAP depletion
Reduce supply of
amyloid
precursor
protein
Stabilise amyloid-
forming proteins
▪ β sheet breakers
Fibril formationFibril formation
Reversion to normally folded protein
Tetramer stabilisers: TafamidisDiflunisalAG10
Liver transplantationGene silencing:• Antisense
oligonucleotides*• Small interfering RNA
PatisiranInotersen
Amyloid deposit clearance• Antibodies• Doxycyline/
TUDCA
SAP, serum amyloid P
In reactive systemic (inflammatory disease, AA) treated vigorouslyReducing the supply of the amyloid fibril precursor protein ->
amyloid regression
Gillmore JD, et al. Lancet 2001;358(9275):24–29; Lachmann HJ, et al. N Eng J Med 2007:356(23);2361–2371; Lachmann HJ, et al. Br J Haematol 2003;122(1):78–84; Palladini G, et al. J Clin Oncol 2012;30(36):4541–4549
serum amyloid P component scintigraphy
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Other treatments for amyloidosis
• Antisense and interfering RNA therapeutics
(patiseran, inotersen)
• Transthyretin tetramer stabilising agents (diflusinal
and tafamidis).
• Monoclonal anti-SAP antibodies (clearance of
established amyloid).
Maurer et al, Circ Heart Fail 2015; Sekijima et al, Society of Amyloidosis 2006; Coelho et al, NEJM 2013; Ackermann et al, the International Society of Amyloidosis 2012; Richards et al, NEJM 2015.
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Other treatments for amyloidosis
• Antisense and interfering RNA therapeutics (reduce
TTR production by 80-90%).
• Transthyretin tetramer stabilising agents (diflusinal
and tafamidis).
• Monoclonal anti-SAP antibodies (clearance of
established amyloid).
Maurer et al, Circ Heart Fail 2015; Sekijima et al, Society of Amyloidosis 2006; Coelho et al, NEJM 2013; Ackermann et al, the International Society of Amyloidosis 2012; Richards et al, NEJM 2015.
TTR-lowering therapy: Alnylam & Ionis/AkceaReduce pre-cursor supply of amyloid through RNAi
ATTR, TTR amyloidosis; LFT, liver function test; RNA interference (RNAi), TTR, transthyretinCoelho T, et al. N Engl J Med 2013;369(9):819–829
Inotersen (Ionis/Akcea)
• A 2′-O-methoxyethyl–modified antisense oligonucleotide, inhibits hepatic production of transthyretin
• Phase 1 – healthy volunteer study
• 80% reduction in plasma TTR concentration
• Transient inflammation, abnormal LFTs
Patisiran (Alnylam)
• Phase 1 – healthy volunteer study
• 85% reduction in plasma TTR concentration
• Mild injection site reactions only toxicity
Rapid, dose-dependent, and durable lowering of mutant and non-mutant
transthyretin levels
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Statistically Significant Benefit in Neuropathy Disease Progression
• mNIS+7 Primary Endpoint
Placebo Inotersen
Baseline (absolute value) 74.12 79.35
Change from baseline to month 15
25.53 5.80
Statistically significant difference was observed at both 8 months and 15 months
LSM = Least Squares Method
02
04
06
08
0
0
5
1 0
1 5
2 0
2 5
3 0
S t u d y W e e k
mN
IS+
7
Ch
an
ge
fr
om
Ba
se
lin
e
(L
SM
S
EM
)
P la c e b o
I n o t e r s e n
1 9 . 7 3
( p = 0 . 0 0 0 0 0 0 0 4 )
8 . 6 9
( p = 0 . 0 0 0 5 )
mNIS+7: Modified neuropathy impairment score +7 neurophysiology tests; The Norfolk Quality of Life‐Diabetic Neuropathy (QOL‐DN) questionnaire
Benson et al. NEJM. 2018; 379: 22-31.
Statistically Significant Benefit in Quality of Life
• Norfolk QoL-DN Primary Endpoint
Statistically significant difference was observed at both 8 months and 15 months
* **
11.68
LSM = Least Squares Method*p = 0.032, **p = 0.0006
Placebo Inotersen
Baseline (absolute value) 48.60 48.57
Change from baselineto month 15
12.67 0.99
Benson et al. NEJM. 2018; 379: 22-31.
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NEURO-TTR: Inotersen - Safety Observations
• Overall death rate (2.9%)• 5 deaths in study: 5 (4.5%) in inotersen arm, 0 in placebo arm
– 4 deaths in the inotersen arm were associated with disease progression and considered unrelated to treatment• Cachexia (2)• Intestinal perforation due to sigmoid volvulus• Congestive heart failure following stoma revision surgery complications
– 1 fatal intracranial hemorrhage in conjunction with serious thrombocytopenia• No serious thrombocytopenia observed following implementation of more
frequent monitoring
• Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring.
*Approved by NICE May 2019 for stage 1 and stage 2 polyneuropathy in adults with hereditary transthyretin amyloidosis
Benson et al. NEJM. 2018; 379: 22-31.
Stages of familial amyloid polyneuropathy
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Patisiran Phase 3 APOLLO Study Results
• 87.8% mean serum TTR Reduction from baseline for patisiran over 18 months
Me
an
[±
SE
M]
Se
rum
TT
R K
no
ck
do
wn
,
%
100
90
80
70
60
50
40
30
20
10
0
-10
Weeks
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
Placebo (N=77)
Patisiran (N=148)
TTR ChangeChange from baseline at 9 months Change from baseline at 18 months
Placebo (N=77) Patisiran (N=148) Placebo (N=77) Patisiran (N=148)
Mean (SEM) Serum TTR Knockdown 1.5% (4.47) 82.6% (1.36) 4.8% (3.38) 84.3% (1.48)
SEM, standard error of mean; TTR, transthyretin. Adams D, et al. N Engl J Med 2018;379(1):11–21
Patisiran APOLLO study results (n=225)
NIS, neurological impairment score; QoL-DN, quality of life-diabetic neuropathy; SEM, standard error of mean; TTR, transthyretinAdams D, et al. N Engl J Med 2018;379(1):11–21
Primary endpoint: mNIS+7 change from baseline
Secondary endpoint: Norfolk QoL-DN change from baseline
TTR changeChange from baseline at 9 months Change from baseline at 18 months
Placebo (n=77) Patisiran (n=148) Placebo (n=77) Patisiran (n=148)
Mean (SEM) serum TTR knockdown 1.5% (4.47) 82.6% (1.36) 4.8% (3.38) 84.3% (1.48)
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Patisiran APOLLO study: Cardiac results
*mITT population; **For any hospitalization/death analysis: negative binomial regression RR 0.49 (0.30, 0.79); Anderson-Gill HR 0.48 (0.34, 0.69); †For cardiac hospitalization/death analysis: negative binomial regression RR 0.54 (0.25, 1.16); Anderson-Gill HR 0.54 (0.28, 1.01) AE, adverse event; CRF, case report form; HR, hazard ratio; RR, rate ratio; SAEs, serious
adverse events; SOC, system organ class. Solomon SD, et al. Circulation 2019;139(4):431–443; Adams D, et al. Presented at American Academy of Neurology 2018; April 2018, Los Angeles, USA
• Mean cumulative function = average number of events per patient by a certain time
• Analysis of hospitalization/death data was conducted post-hoc based on data collected from AE CRFs; hospitalization/death events caused by SAEs within 28 days of last dose of study drug were included; hospitalization events caused by SAEs within SOC of cardiac disorder were classified as cardiac hospitalization
Recurrent hospitalization and death events by treatment arm (post-hoc analysis)*
Approximately
50% reduction in
event rate**
Approximately
45% reduction
in event rate†
Treatment strategies in (ATTR) amyloidosis
Precursor proteinPrecursor protein AmyloidAmyloid
Therapeutic strategies in amyloidosis
Enhance removal of
existing amyloid
▪ Immunotherapy
▪ SAP depletion
Reduce supply of
amyloid
precursor
protein
Stabilise amyloid-
forming proteins
▪ β sheet breakers
Fibril formationFibril formation
Reversion to normally folded protein
TafamidisDiflunisalAG10
Liver transplantationPatisiranInotersen
SAP, serum amyloid P
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Treatment
ClinicalTrials.gov number, NCT01994889. Maurer MD, et al. NEJM. 2018; 379: 1007-1016
Maurer MD, et al. NEJM. 2018; 379: 1007-1016
Tafamidis treatment for patients with TTR amyloid
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UK ‘state of play’ with new drugs for hATTRamyloidosis
• Patisiran (TTR-lowering)
• Inotersen (TTR-lowering)
• Tafamidis (stabilizer)
• Diflunisal (stabilizer)
MA by FDA & EMA, Aug 2018 (hATTR with stage I/II PN)
NICE HST evaluation, Approved August 2019
Available in NHS since Dec 2019
MA by EMA, July 2018 (stage I/II PN in hATTR amyloidosis)
MA by FDA, Oct 2018
NICE HST evaluation, Approved May 2019
Available in NHS via NAC since August 2019
MA by EMA for hATTR neuropathy, 2011 (MA not granted by FDA)
Not funded in UK (few patients with V30M, efficacy modest)
But recent +ve ATTR-ACT trial in cardiac ATTR amyloidosis; resubmission in progress
EAMS for cardiac ATTR amyloidosis in progress, NICE appraisal expected July 2020
Available and used in UK (but supplies unreliable and poorly tolerated)
(h)ATTR, (hereditary) TTR amyloidosis; TTR, transthyretin
Trials and EAMS of ‘new drugs’ for cardiac ATTR amyloidosis
• ATTRibute-CM – Phase 3 clinical trial of AG10 (stabilizer)
– Recruiting in UK, n = 510 patients (2:1 drug:placebo)
• Early Access to Medicine Scheme (EAMS) of tafamidis (stabilizer)
– Open in UK, n = 130 patients (no placebo)
– Recent +ve ATTR-ACT trial in ATTR-CM – submission to NICE for funding, 2019
• APOLLO-B – Phase 3 clinical trial of patisiran (TTR-lowering)
– End 2019, n = 300 patients (1:1 placebo controlled)
• HELIOS-B - Phase 3 trial of vitrisiran (2nd generation TTR-lowering)
– In planning (2020), n = 600 patients (1:1 placebo controlled)
• ION-CS2 - Phase 3 trial of ION-682884 (2nd generation TTR-lowering)
– In Planning (2020), n = 700 patients (1:1 placebo controlled)
ATTR-CM, TTR amyloidosis cardiomyopathy; TTR, transthyretin
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‘Hope for the heart’
Summary
• Diagnosis and typing of amyloid remains challenging
• Key to detection is a high level of suspicion
• ATTR amyloidosis is increasingly recognised & diagnosed
• Integrate all clinical information including patient demographics, race, gender, mode of presentation, ECG, echo and CMR, DPD and urine/serum analysis + FLC
• Diagnosis of ATTR-CM has been enhanced by CMR and bone scintigraphy
– More than two thirds of patients now diagnosed non-invasively
• But delays in diagnosis persist
– Earlier diagnosis of cardiomyopathy +/- via extra-renal manifestations
– Red flags & awareness, awareness (education)
• Simple staging systems can prognosticate and stratify enrolment of patients with ATTR amyloidosis into trials of novel ‘disease-modifying’ therapies
• Diagnosis is important to allow for effective patient management
ATTR-CM, TTR amyloidosis cardiomyopathy; CMR, cardiac magnetic resonance imaging; ECG, electrocardiogram; Echo, echocardiogram; TTR, transthyretin
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Current amyloidosis patient pathway
Newly diagnosed patient with amyloidosis
or suspicion of amyloidosis
Refer to Local Amyloid Clinic or National
Amyloidosis Centre for diagnostic assessment and
treatment recommendation
Confirmation of diagnosis, type and treatment
plan locally or at National Amyloidosis Centre
Treatment and follow-up with referring clinician
Follow-up every 6–12 months
Local follow-up every 1–3 months
after completing treatment
When do I need to suspect ATTR-CA?
• Family history of ATTR amyloidosis
• Diagnosis of polyneuropathy due to ATTR amyloidosis
• Hypotension in a patient with previous hypertension
• Intolerance to commonly used cardiovascular
medications
• Evidence of right-sided or biventricular heart failure
• Referral for placement of pacemaker
ATTR-CM, transthyretin amyloid cardiomyopathy. Dharmarajan K, Maurer MS. J Am Geriatr Soc. 2012;60:765–74.
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Diagnostic algorithm
AApoA1, apolipoprotein A-I; AL, amyloidosis light chain; ATTR, TTR amyloidosis; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; HDMP, hydroxymethylene diphosphonate; PYP, pyrophosphate; TTR, transthyretin. Gillmore JD, et al. Circulation 2016;133(24):2404–2412
Take home messages
• Not all cardiac amyloidosis is AL type
• Identifying the amyloid type is essential to guide treatment and determine prognosis
• The diagnosis of cardiac amyloidosis is often delayed
• The finding of hereditary ATTR amyloidosis has implications for family screening
• With a combination of peripheral neuropathy and cardiac failure – think amyloid!
• Screen by gene sequencing (TTR) and DPD scan (available locally)
• DPD scan can be positive in AL as well as TTR cardiac amyloid
• MDT approach with good communication with patients and relatives and between teams is essential
• Novel TTR-lowering therapy effective and is now available
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Summary
• Exciting times in ATTR amyloidosis!
• Several drugs in late phase development
– TTR-lowering therapy
– TTR-stabilizing therapy
• 2nd generation (better) TTR-lowering drugs already in development
• Combination therapy with TTR-lowering + TTR Stabiliser is (theoretically) attractive
• New ‘National’ management pathway for amyloidosis in development with NHS-E
Future challenges
• Earlier diagnosis and reducing diagnostic delays
• When to treat/which treatments
• Monitoring treatments
• Complications of successful treatments
• Costs/global access
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• Thank you
• Any questions?
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