Transthyretin Cardiac Amyloidosis

Index of suspicion ATTR-CM

History

Cardiac manifestations

Fatigue

Heart failure symptoms

Severe AS

Family Hx of heart failure

Conduction system disease/pacemaker

Atrial fibrillation

Extracardiac manifestations

Bilateral carpal tunnel syndrome

Lumbar/cervical spinal stenosis

Spontaneous biceps tendon rupture

Hip or knee replacement

Sensory peripheral neuropathy

Family history of neuropathy

Autonomic dysfunction

AL-amyloid

Extracardiac manifestations

Renal dysfunction, proteinuria
Carpal tunnel
Hepatic dysfunction
Orthostatic hypotension
Peripheral neuropathy
Gastrointestinal abnormalities
Hypothyroidism
Macroglossia
Periorbital purpura

Laboratory test results

Persistent low levels of troponin elevation

Elevated natriuretic peptides

ECG

Low voltage to LV mass ratio

(low QRS voltage on electrocardiogram (ECG) is not sensitive and only observed in 25% to 40% of cases of ATTR-CM.)
Atrial fibrillation/flutter, especially with controlled ventricular response

Conduction delay (atrioventricular block ± intraventricular conduction delay)

Pseudoinfarct pattern

Echocardiography

2-Dimensional imaging
Increased LV and RV wall thickness
Interatrial septal and diffuse valve thickening
RV hypertrophy
Pericardial effusion
Biatrial enlargement and dysfunction
Preserved EF with low stroke volume index

Doppler
Reduced tissue Doppler s’, e’, and a’ velocities
Restrictive transmitral Doppler filling pattern
Diastolic dysfunction grade 2 with high E/A ratio (> 1.5) and reduced E deceleration time (< 150 ms)
Reduced TAPSE

Other
Reduced global longitudinal strain; ratio between EF and global longitudinal strain
Apical sparing on 2-dimensional speckle tracking images (classically referred to as “cherry on top”)
Low flow, low-gradient severe aortic stenosis
Impaired left atrial strain

Cardiac MRI

Diffuse subendocardial or transmural late gadolinium enhancement
Increased myocardial native T1
ECV expansion (>40%)
Reversal of nulling (nulling of the myocardium before or at the same inversion time as blood pool)

Diagnostic Algorithm for Cardiac Amyloidosis

History, ECG, and imaging suggestive of cardiac amyloidosis.

Evidence of monoclonal protein

Monoclonal protein in serum/urine IFE
Abnormal serum kappa/lambda free light chain depends on eGFR (See below)
SPEP/UPEP not as sensitive as IFE

Positive

Negative

Consult Hematologist

Biopsy (affected organ, surrogate site)

Positive Congo Red
Tissue typing by mass spectrometry

AL-CM or

ATTR-CM with MGUS

Radionuclide scintigraphy (with SPECT)

• Grade 2/3 uptake

Yes

ATTR-CM

Cardiac amyloid is unlikely

Genetic testing

ATTRv-CM

ATTRwt-CM

Biopsy sensitivity

Reference K/L ratio (depends on eGFR)

Amyloid Type	Fat pad sensitivity	Bone marrow sensitivity
AL	73-84%	60%
ATTRv	45-67%	41-47%
ATTRwt	14-16%	30-38%

eGFR	Free light chain ratio range
45-59	0.46-2.62
30-44	0.48-3.38
15-29	0.54-3.30
<15	0.54-3.30

Genotype–phenotype correlation in ATTR amyloidosis.

V30M Early-Onset

V28M

G54G

I107P

S77Y

L58H

F33L

E39L

C10R

S50R

R34T

G47A

F64L

A36P

T49A

A97S

V30M Late-Onset

P24S

E89Q

I107V

W41L

T60A

H88R

V20I

A45T

G65L

S23N

I84A

I68L

L111M

V122I

ATTR Wide Type

FDA approved disease-modifying therapies for ATTR-CM

	Tafamidis	Acoramidis	Vutrisiran
Mechanism of action	Transthyretin stabilzer at T4 binding site	Transthyretin stabilzer at T4 binding site	siRNA TTR gene silencer
Landmark trial	ATTR-ACT	ATTRIbute-CM	HELIOS-B
Study design	RCT versus placebo phase 3	RCT versus placebo phase 3	RCT versuss placebo phase 3
Study dose	20 mg or 80 mg orally OD	800 mg orally twice a day	25 mg subcutaneous every 3 mo
FDA-approved dose	tafamidis 61 mg or	712 mg twice daily	25 mg subcutaneous every 3 mo
	tafamidis meglumine 80 mg		in a healthcare setting
No. of participants	441	632	654
Mean age, year	74	77	77
Male, %	90	90	93
ATTRwt/ATTRv	76%/24%	90%/10%	88%/12%
NYHA class (I/II/III)	8/60/32	11/72/17	13/78/9
Primary outcome	Death, CV hospitalizations win ratio:	Death, CV hospitalizations, NT-proBNP	Death, CV events:
	1.7 (95%CI, 1.3-2.3)	change, 6MWT change win ratio:	HR: 0.72 (95%CI: 0.56-0.93)
		1.8 (95%CI, 1.4-2.2)
Vitamin A supplement	Not required	Not required	Vitamin A supplement (local RDA)

Diflunisal (TTR stablizer)

FDA approved as NSAID, Off-label use in ATTRwt or ATTRv with cardiomyopathy or neuropathy

Dose: 250 mg orally twice daily with PPI

Clinical trial: Diflunisal trial Consortium

Inclusion:

ATTRv with sensorimotor polyneuropathy (familial amyloid polyneuropathy)

Biopsy-proven amyloid deposit

Confirm TTR mutation

Exclusion

NYHA class IV

CrCl < 30 ml/min

Anticoagulation

Adverse effect: Fluid retention, Renal dysfunction, Bleeding
Monitoring: Renal function, platelet count, Hemoglobin

Patisiran (TTR Silencer)

FDA approved: ATTRv with neuropathy

Off-label use in ATTRwt or ATTRv with cardiomyopathy or neuropathy

Dose: 0.3 mg/kg intravenously every 3 wk, Premedication with corticosteroids, H1 blocker, H2 blocker, Daily vitamin A supplement

Clinical trial: Apollo Trial

Inclusion:

Documented TTR mutation
Confirmed ATTRv with polyneuropathy
NIS score 5-130
PND score <=3b

Exclusion

NYHA class III-IV
Liver transplantation

Adverse effect: Infusion-related reaction, Vitamin A deficiency
Monitoring: None

Inotersen (TTR silencer)

FDA approved: ATTRv with neuropathy

Dose: 284 mg/wk subcutaneously, Daily vitamin A supplement

Clinical trial: NEURO-TTR

Inclusion:

ATTRv with polyneuropathy stage 1 and 2
NIS 10 - 130
Documented TTR mutation
Documented amyloid deposit on biopsy

Exclusion

Platelets <125 x 10^9/L
CrCl < 60 ml/min 1.73 m2
NYHA class III symptom
Liver transplantation

Adverse effect: Thrombocytopenia, Glomerulonephritis, Infusion-related reaction, Vitamin A deficiency
Monitoring: Weekly platelet count, every 2 wk, serum creatinine, eGFR, UPCR

Reference

1) Writing Committee; Kittleson MM, Ambardekar AV, Cheng RK, Griffin JM, Maurer MS, Nativi-Nicolau J, Ruberg FL. Transthyretin Cardiac Amyloidosis Evaluation and Management: 2025 ACC Concise Clinical Guidance. J Am Coll Cardiol. 2026 Feb 10;87(5):549-565. doi: 10.1016/j.jacc.2025.09.004. Epub 2025 Oct 31. PMID: 41171219.

2) Poli L, Labella B, Cotti Piccinelli S, Caria F, Risi B, Damioli S, Padovani A and Filosto M (2023) Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy. Front. Neurol. 14:1242815. doi: 10.3389/fneur.2023.1242815