Cardiac Amyloidosis

11/02/2020

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 Kidney damage with proteinuria, low albumin, hyperlipidaemia, +++ oedema Complications: blood clots, HTN, infections • 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)

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

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Case 1

Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 months Stage 2: one or other marker high survival 10.5 months • Both renal biopsies stained Stage 3: both markers high survival 3.5 months – 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

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 -ve DPD, +ve screen -ve DPD, -ve screen

TTR cardiac amyloid likely AL amyloid possible Consider alternative diagnosis

1. Offload 1. Offload 2. Refer ICC clinic/NAC 2. Liaise NAC and Haem as IP 3. Discharge 3. Consider endomyocardial biopsy 4. Look for other organ involvement

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, transthyretin Gillmore JD, et al. Circulation 2016;133(24):2404–2412 19

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-STOPmnemonic for initial steps in CA: C: conduction and rhythm disorder prevention (amiodarone = ok, pacemaker) H: high heart rate maintenance A: anticoagulation D: diuretics STOP: 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 type Amyloid fibril protein (circulating) • AL • Light chain of immunoglobulin • AA • Amyloid A protein • ATTRwt • ‘Normal’ TTR • hATTR • ‘Mutated’ TTR There are more than 30 known amyloid fibril proteins!

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 misfolding • 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

Time from 1st Symptom to diagnosis of ATTR-CM 100 1 attendance 80 2 attendances 3 attendances 60

42% 40

23% patients of Percentage 0 ER IP OP ER IP OP ER IP OP Year -3 Year -2 Year -1 35% Median 17 hospital attendances prior to diagnosis! CATEGORY 1 Median 3 hospital IP episodes prior to diagnosis 0-6 months 6 months-4 yrs >4 years 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-type Gertz 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;7:531-2 3 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 46 TTR mutations in the UK – Variable penetrance and phenotype, including: 70.5% T60A CTS (-7.5, 13-0) • peripheral & autonomic neuropathy • amyloid cardiomyopathy 22% T60A V30M • vitreous amyloid deposits 47% G47V 6% V122I • leptomeningeal disease 6% E89K 5% Other Several single amino acid substitutions associated: 14% • 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

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TTR mutations

• 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

TTR, transthyretin

Genotypic-phenotypic correlation in ATTR amyloidosis

V30M and V122I: most common mutations worldwide1 Most prevalent variants in UK:2 T60A: 30% V122I: 64%

Figure adapted from Rapezzi C. et al. Eur Heart J 2013;34:520–8 by permission of Oxford University Press 1. 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

100 ATTRwt 80 ATTR T60A ATTR V122I 60 AL

Percent survival 20

0 0 12 24 36 48 60 Time (months)

Median survival in cardiac AL ~12 months Median 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 Secondary Restrictive Cardiomyopathy Cardiomyopathy

Endomyocardial Infiltrative Disease Storage Disease Fibrosis

Loeffler’s Cardiomyopathy Amyloidosis Hemochromatosis

Idiopathic Restrictive Glycogen Storage Sarcoidosis Cardiomyopathy Disease

Postirradiation Fabry’s Disease Therapy

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

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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

Ocular manifestations • Vitreous opacification CNS manifestations • *Periorbital ecchymosis • Progressive dementia • Glaucoma • Headache • Abnormal conjunctival vessels • Ataxia • Papillary abnormalities • Seizures • Spastic paresis • Stroke-like episodes *Macroglossia Cardiovascular manifestations • Conduction blocks • Cardiomyopathy • Palpitations and arrhythmia • Mild regurgitation GI manifestations • Shortness of breath • Oedema • *Organomegaly • Nausea and vomiting • Changes in GI motility (i.e. diarrhoea, constipation, gastroparesis, early satiety) • Unintentional weight loss Autonomic neuropathy • Orthostatic hypotension • Recurrent UTI (due to urinary retention) Renal manifestations • Sexual dysfunction • Sweating abnormalities • Proteinuria • Renal failure

Connective tissue Peripheral sensory motor neuropathy • Carpal tunnel syndrome • Neuropathic pain • Spinal Stenosis • Altered sensation (i.e. change in sensitivity to pain and temperature) Myopathy • Numbness and tingling • Muscle weakness • Impaired balance • Difficulty walking *Very suggestive of AL amyloidosis AL, amyloidosis light chain; CNS, central nervous system; GI, gastrointestinal; UTI, urinary tract infection Based on Conceição et al. J Peripher Nerv Syst 2016;21(1):5–9

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

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ECG: What to look for

• QRS meeting the voltage criteria • Conduction abnormalities, including 1,2 • Low QRS voltage1,2 bundle branch block • Rhythm disturbances (e.g. atrial fibrillation)1,2 • Pseudo-infarction patterns of Q wave1

Common findings in ECG traces from patients with Val122Ile hATTR amyloidosis1

Sinus bradycardia with first-degree atrioventricular Atrial fibrillation, anterolateral block, low QRS voltage and inferior infarcts (pseudo- and poor precordial infarcts) R-wave progression

Sinus rhythm with marked first- Marked sinus bradycardia, degree atrioventricular block, inferior infarct low QRS voltage and left bundle (pseudo-infarct) branch block

ECG, electrocardiogram; hATTR, hereditary TTR amyloidosis; TTR, transthyretin Figure reproduced with permission from Dharmarajan K, Maurer MS. J Am Geriatr Soc 2012;60(4):765–774 1. 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

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 Parasternal long axis Parasternal short axis • 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

a Restrictive transmitral Tissue Doppler: reduced Reduced S’ and E’ velocities, respectively Doppler pattern longitudinal systolic shortening AL, amyloidosis light chain; ATTR, TTR amyloidosis; RV, right ventricular; TTR, transthyretin and diastolic dysfunctiona

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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?

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

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

Stage 1: both markers low (NT-proBNP <332, TnT <0.035, TnI <0.1) median survival 26.4 months Stage 2: one or other marker high survival 10.5 months Stage 3: both markers high survival 3.5 months

A raised NT-proBNP and TnT or TnI are predictive of adversity

Diagnosis – CMR, ETT, Holter

Exercise ECG MRI scan

CPET

Holter monitor

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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis

CMR: What to look for

• LGE imaging is used to identify amyloid infiltration directly1

No LGE Subendocardial LGE Transmural LGE

CMR, cardiac magnetic resonance imaging; LGE, late gadolinium enhancement Figure reproduced with permission from Fontana M, et al. Circulation 2015;132(16):1570–1579 1. 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, transthyretin Fontana M, et al. JACC Cardiovasc Imaging 2014;7(2):157–165

Native T1 in the hypertrophic phenotype

HCM, hypertrophic cardiomyopathy Sado DM, et al. Circ Cardiovasc Imaging 2013;6(3):392–398

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Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis

DPD scintigraphy: 99mTc-DPD uptake in cardiac ATTR amyloidosis1,2

Grade 0 Grade 1 Grade 2 Grade 3

• 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 Bone Cardiac ATTR amyloidosis Positive - >99% sensitive Grade 2/3 – 90% specific 99mTc-DPD, technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid; ATTR, TTR amyloidosis; TTR, transthyretin 1. 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 77

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Cardiac uptake on DPD Amyloidosis

No Cardiac uptake on DPD No amyloidosis

Cardiac uptake on DPD only ATTR 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

Clinical case

• 70-year old gentleman with SOB and oedema, echo showed increase in LV mass (septum)

MGUS

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

Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis

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SAP scintigraphy following OLT in FAP can monitor regression of visceral amyloid

Before OLT +15 months +36 months

FAP, familial amyloid polyneuropathy; OLT, orthotopic liver transplantation; SAP, serum amyloid P

Diagnostic Pathway of Cardiac Amyloidosis: Investigations and diagnosis

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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 sensitivity Gillmore 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

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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

•CHADTreat- STOPunderlyingmnemonic cause (iffor identified) initial steps in CA: •C:Diuretics conduction as needed and rhythm -> offload disorder acutely prevention •(amiodaroneLong term usual = ok, fluid pacemaker) balance advice •H:Little high role heart for rate ACEi maintenance, ARBs, BBs, rate limiting CCBs •A:Digoxin anticoagulation controversial •D:Rhythm diuretics control STOP:– Amiodarone STOP betablockers and calcium channel blockers (to •optimize?Disease HR,-modifying CO and meds preload), unproven STOP digoxin and STOP •reninAnticoagulation-angiotensin-aldosterone inhibitors (to minimize • Autonomic neyropathy therefore tend to avoid ACEi or beta- severeblockers hypotension, unless already esp takingin autonomic them and dysfunction asymptomatic – unless •alreadyAdvanced taking HF therapiesthem 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 Therapeutic strategies in amyloidosis

Precursor protein Amyloid Reversion to normally folded protein

Liver transplantation Gene silencing: Fibril formation Tetramer • Antisense stabilisers: oligonucleotides* Tafamidis • Small interfering RNA Diflunisal AG10 Patisiran Stabilise amyloid- Inotersen forming proteins

▪ β sheet breakers Enhance removal of Amyloid existing amyloid deposit Reduce supply of clearance amyloid ▪ Immunotherapy • Antibodies precursor ▪ SAP depletion • Doxycyline/ protein TUDCA

SAP, serum amyloid P

Gene silencing: • Small interfering RNA

Tetramer stabiliser

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Treatment strategies in (ATTR) amyloidosis Therapeutic strategies in amyloidosis

Precursor protein Amyloid Reversion to normally folded protein

▪ β sheet breakers Enhance removal of Amyloid existing amyloid deposit Reduce supply of clearance amyloid ▪ Immunotherapy • Antibodies precursor ▪ SAP depletion • Doxycyline/ protein TUDCA

SAP, serum amyloid P

In reactive systemic (inflammatory disease, AA) treated vigorously Reducing the supply of the amyloid fibril precursor protein -> amyloid regression

serum amyloid P component scintigraphy 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

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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.

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TTR-lowering therapy: Alnylam & Ionis/Akcea Reduce pre-cursor supply of amyloid through RNAi

Rapid, dose-dependent, and durable Inotersen (Ionis/Akcea) lowering of mutant and non-mutant transthyretin levels • 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

ATTR, TTR amyloidosis; LFT, liver function test; RNA interference (RNAi), TTR, transthyretin Coelho T, et al. N Engl J Med 2013;369(9):819–829

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Statistically Significant Benefit in Neuropathy Disease Progression

• mNIS+7 Primary Endpoint

Statistically significant difference was observed at both 8 months and 15 months

3 0

P la c e b o Placebo Inotersen

2 5 I n o t e r s e n

l e

) Baseline (absolute value) 74.12 79.35

s 2 0

7 E

B 1 9 . 7 3

m ( p = 0 . 0 0 0 0 0 0 0 4 ) I  1 5

o Change from baseline to

f M

25.53 5.80

S e

m month 15

L g ( 1 0

n 8 . 6 9 a

h ( p = 0 . 0 0 0 5 ) C 5

0 0 0 0 0 2 4 6 8

S t u d y W e e k LSM = Least Squares Method

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.

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Statistically Significant Benefit in Quality of Life

• Norfolk QoL-DN Primary Endpoint

Statistically significant difference was observed at both 8 months and 15 months

Placebo Inotersen

Baseline (absolute value) 48.60 48.57 11.68

Change from baseline 12.67 0.99 * ** to month 15

LSM = Least Squares Method *p = 0.032, **p = 0.0006

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.

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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

-10 10

0 0

10 -10

20 -20

30 Placebo (N=77) -30

40 Patisiran (N=148) -40 % 50 -50

60 -60

70 -70 SEM] Serum TTR Knockdown, Serum TTR SEM]Knockdown,

± 80 -80

90 -90 Mean[ 100 -100

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 Weeks Change from baseline at 9 months Change from baseline at 18 months TTR Change 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

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Patisiran APOLLO study results (n=225)

Primary endpoint: mNIS+7 change Secondary endpoint: Norfolk QoL- from baseline DN change from baseline

Change from baseline at 9 months Change from baseline at 18 months TTR change 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)

NIS, neurological impairment score; QoL-DN, quality of life-diabetic neuropathy; SEM, standard error of mean; TTR, transthyretin Adams D, et al. N Engl J Med 2018;379(1):11–21

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Patisiran APOLLO study: Cardiac results

Recurrent hospitalization and death events by treatment arm (post-hoc analysis)*

Approximately 50% reduction in Approximately event rate** 45% reduction in event rate†

• 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

*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

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Treatment strategies in (ATTR) amyloidosis Therapeutic strategies in amyloidosis

Precursor protein Amyloid Reversion to normally folded protein

Liver transplantation Patisiran Fibril formation Tafamidis Inotersen Diflunisal AG10

Stabilise amyloid- forming proteins

▪ β sheet breakers Enhance removal of existing amyloid Reduce supply of amyloid ▪ Immunotherapy precursor ▪ SAP depletion protein

SAP, serum amyloid P

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Treatment

ClinicalTrials.gov number, NCT01994889. Maurer MD, et al. NEJM. 2018; 379: 1007-1016

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Tafamidis treatment for patients with TTR amyloid

Maurer MD, et al. NEJM. 2018; 379: 1007-1016

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UK ‘state of play’ with new drugs for hATTR amyloidosis

• Patisiran (TTR-lowering) MA by FDA & EMA, Aug 2018 (hATTR with stage I/II PN) NICE HST evaluation, Approved August 2019 Available in NHS since Dec 2019

• Inotersen (TTR-lowering) 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

• Tafamidis (stabilizer) 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

• Diflunisal (stabilizer) Available and used in UK (but supplies unreliable and poorly tolerated)

(h)ATTR, (hereditary) TTR amyloidosis; TTR, transthyretin

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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’

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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

Local follow-up every 1–3 months after completing treatment

Follow-up every 6–12 months

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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

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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

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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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