Cardiac Amyloidosis · 2020-02-11 · 11/02/2020 1 Cardiac Amyloidosis General Medicine for Palliative Physicians Conference 2020 Dr Eleanor Wicks Clinical Lead of Inherited Cardiac

11/02/2020

1

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

1

2

11/02/2020

2

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

3

4

11/02/2020

3

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


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 +++

5

6

11/02/2020

4

CXR

ECG

7

8

11/02/2020

5

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

9

10

11/02/2020

6

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.

11

12

11/02/2020

7

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

13

14

11/02/2020

8

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

15

16

11/02/2020

9

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

17

18

11/02/2020

10

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

19

20

11/02/2020

11

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?

21

22

11/02/2020

12

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

23

24

11/02/2020

13

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

25

26

11/02/2020

14

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.

27

28

11/02/2020

15

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

29

30

11/02/2020

16

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

31

32

11/02/2020

17

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;

33

34

11/02/2020

18

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

35

36

11/02/2020

19

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

37

38

11/02/2020

20

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)

39

40

11/02/2020

21

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

41

42

11/02/2020

22

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.

43

44

11/02/2020

23

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

46

47

11/02/2020

24

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

48

49

11/02/2020

25

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

50

51

11/02/2020

26

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
















• Bioimpedance




52

53

11/02/2020

27

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• …

54

55

11/02/2020

28

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

56

57

11/02/2020

29
















• Bioimpedance




58

59

11/02/2020

30

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

60

61

11/02/2020

31

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

62

63

11/02/2020

32
















• Bioimpedance




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

64

65

11/02/2020

33

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

66

67

11/02/2020

34
















• Bioimpedance




Additional basic investigations

• To derive type of amyloid

• To assess risk from amyloid

• To assess symptom limitation

68

69

11/02/2020

35

Cardiac biomarkers ATTR: NT-proBNP

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



Diagnosis – CMR, ETT, Holter

Exercise ECG MRI scan

Holter monitor

CPET

70

71

11/02/2020

36
















• Bioimpedance




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

72

73

11/02/2020

37

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

74

75

11/02/2020

38
















• Bioimpedance




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

76

77

11/02/2020

39

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

78

79

11/02/2020

40



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

80

81

11/02/2020

41


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
















• Bioimpedance




82

83

11/02/2020

42

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
















• Bioimpedance




84

85

11/02/2020

43

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.

86

87

11/02/2020

44

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

88

89

11/02/2020

45

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
















• Bioimpedance




91

92

11/02/2020

46

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

93

94

11/02/2020

47

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

95

96

11/02/2020

48

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

97

98

11/02/2020

49




Enhance removal of

existing amyloid

▪ Immunotherapy

▪ SAP depletion

Reduce supply of

amyloid

precursor

protein

Stabilise amyloid-

forming proteins




Tetramer stabilisers: TafamidisDiflunisalAG10

Liver transplantationGene silencing:• Antisense

oligonucleotides*• Small interfering RNA

PatisiranInotersen

Amyloid deposit clearance• Antibodies• Doxycyline/

TUDCA


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

99

100

11/02/2020

50

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).


101

102

11/02/2020

51

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).


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

103

104

11/02/2020

52

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.

105

106

11/02/2020

53

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

107

108

11/02/2020

54

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)

109

110

11/02/2020

55

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†




Enhance removal of

existing amyloid

▪ Immunotherapy

▪ SAP depletion

Reduce supply of

amyloid

precursor

protein

Stabilise amyloid-

forming proteins




TafamidisDiflunisalAG10

Liver transplantationPatisiranInotersen


112

113

11/02/2020

56

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

114

116

11/02/2020

57

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

120

121

11/02/2020

58

‘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

122

123

11/02/2020

59

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.

124

125

11/02/2020

60



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

126

127

11/02/2020

61

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

128

129

11/02/2020

62

• Thank you

• Any questions?

130

Documents

Cardiac Amyloidosis · 2020-02-11 · 11/02/2020 1 Cardiac Amyloidosis General Medicine for Palliative Physicians Conference 2020 Dr Eleanor Wicks Clinical Lead of Inherited Cardiac