AMYLOIDOSIS AND HEART

MATJAŽ KLEMENC

AMYLOIDOSIS OR AMYLOIDOSES?

Various localisations – various clinical patterns

Multi organ disease, with a prognosis

driven by heart involvement

Mahmood et al: Hematologica 2014; 99(2): 209-221.

Wechalekar et al: The Lancet 2016; 387: 2641-53.

AMYLOIDOSIS OR AMYLOIDOSIS ?

Various precursos = various types of amyloidosis

Mahmood et al: Hematologica 2014; 99(2): 209-221.

Wechalekar et al. The Lancet 2016; 387: 2641-53.

Transthyretin: a transport protein - thyroxine

and retinol , created in the liver

AL AMYLOIDOSIS

• LC fibrils infiltrate the

myocardium,

• interfere with cell–cell coupling,

• disrupt cellular integrity

• and may contribute to cell injury

and death

• LC monomers also can elicit

oxidative damage by interacting

with proteins involved in cell

viability and metabolism

AL AMYLOIDOSIS

• Sudden death in patients with AL amyloidosis is usually attributed

to:

• pulseless electrical activity → ventricular arrhythmias,

• thromboembolic complications

• bradyarrhythmias

• conduction system disease secondary to amyloid infiltration

• autonomic dysfunction

Grogan M, Dispenzieri A. Natural history and therapy

of AL cardiac amyloidosis. Heart Fail Rev 2015;20:155–62.

CLUES TO DIAGNOSIS OF AL AMYLOIDOSIS

• heart failure associated with neuropathy

• nephrotic syndrome

• hepatomegaly

• periorbital bleeding

• macroglossia

symptoms of cardiac AL amyloidosis

may mimic those of other restrictive

cardiomyopathies

CONFIRMATION OF DIAGNOSIS

• detection of amyloid in organ or other tissue biopsy using Congo red or

other histological staining

• cardiac biopsy conclusively identifies cardiac AL amyloidosis

• assessment of amyloid from periumbilical fat aspirates or from bone

marrow or labial salivary gland biopsy specimens is a less invasive

approach (sensitivity ≈ 80% in experienced centers)

• accurate amyloid typing* is critical because treatment of cardiac

amyloidosis depends entirely on amyloid type

*… gold standard of amyloid typing is

to determine the precursor protein using

laser microdissection mass spectrometry.

ALGORITHM FOR DIAGNOSIS IN PATIENTS WITH SUSPECTED CARDIAC AMYLOIDOSIS

Gertz M et al, Nat Rev Cardiol 2015;12:91–102

ALGORITHM FOR DIAGNOSIS IN PATIENTS WITH AMYLOIDOSIS ESTABLISHED BY BIOPSY

Gertz M et al, Nat Rev Cardiol 2015;12:91–102

CONSENSUS CRITERIA FOR ORGAN INVOLVEMENT - HEART

• Diagnostic criteria*:

• mean LV wall thickness >12 mm in diastole on echocardiography (no other

cardiac cause)

• elevated NT-proBNP (>332 ng/L) in the absence of renal failure or atrial

fibrillation

*Non-invasive diagnostic criteria in patients for whom

a diagnosis of systemic amyloidosis has been made

by tissue biopsy; once the diagnosis of systemic

amyloidosis has been established, biopsy of organs to

determine extent of involvement is not recommended.

STRUCTURE OF TTR AND FORMING OF FIBRILS

Ruberg: JACC 2019

hereditary ATTR-CM: mutation in the transthyretin gene, which

results in amyloid deposits in the heart, nerves and sometimes

the kidneys and other organs, symptoms may start as early as

age 20 or as late as age 80.

wild-type ATTR-CM: no mutation in the transthyretin gene,

most commonly affects the heart and can also cause carpal

tunnel syndrome and peripheral neuropathy (pain and

numbness in the hands and feet), symptoms usually start after

age 65.

GENOTYPE - PHENOTYPE IN TTRA

“neurological” “cardiac”

phenotype

Rapezzi C in sod: European Heart Journal (2013) 34, 520–528

COMPARISON OF CAUSES, CLINICAL PRESENTATION AND CLINICAL OUTCOME

Grogan M, et al. Heart2017;103:1065–1072

ECG AND AMYLOIDOSIS

CARDIAC CONSEQUENCES OF INFILTRATION

• MYOCARDIAL DEPOSITS:

• wall thickening

• diastolic +/- systolic dysfunction

• elevated troponin

HFpEF

CARDIAC COSEQUENCES OF INFILTRATION

difuse segmental subendocardial

Leone O et al. Amyloid 2012; 19(2): 99-105

CHANGES OF THE HEART BECAUSE OF INFILTRATION

• VALVULAR DEPOSITS:

• tricuspid regurgitation

• mitral regurgitation

• aortic stenosis (low

gradient)

CHANGES OF THE HEART BECAUSE OF INFILTRATION

• MYOCARDIAL DEPOSITS:

• wall thickening

• diastolic +/- systolic dysfunction

• elevated troponin

• VALVULAR DEPOSITS:

• trikuspid regurgitation

• mitral regurgitaton

• aortic stenosis (low gradient)

• ATRIAL DEPOSITS:

• supraventricular arrhytmias

• PERICARDIAL DEPOSITS:

• pericardial effusion

• CONDUCTION SYSTEM:

• AV / bundle branch block

• CARDIAC DYSAUTONOMIA:

• postural hypotension

• INTRA-VASCULAR DEPOSITS:

• ischaemia, thrombosis

DYSAUTONOMIA : CARDIOVASCULAR SYSTEM

Palma JA et al: CAR 2019

impaired baroreflex mediated

sympathetic activation

neurogenic orthostatic

hypotension

MORPHOLOGICAL PRESENTATIONS

• wall thickening

• systolic dysfunction

• diastolic dysfunction

• damages of the valves

• CARDIAC ULTRASOUND:

CARDIAC ULTRASOUND

SYSTOLE DIASTOLE

GLOBAL LONGITUDINAL STRAIN (GLS)

GLS AND AMYLOIDOSIS

HCM AL TTRA

MORPHOLOGICAL PRESENTATION: CMR

LGE – PSIR : CARDIAC AMYLOIDOSIS

Fontana M, Circulation 2015

Without LGE subendocardial transmural

PSIR: phase sensitive inversion recovery

THROMBUS IN LEFT ATRIAL APPENDAGE

MORPHOLOGICAL PRESENTATION

• SCINTIGRAPHY:

• myocardial uptake of bone tracer

• myocardial defect with MIBG (meta-iodobenzylguanidine)

• 11C-Pittsburgh B compound (N-[methyl-11C]2-(49-methylamino-phenyl)-6-

hydroxybenzothi-azole ) and florbetapir can specifically bind

cardiac amyloid and may be useful when combined with

structural and functional imaging assessments

• 99mTc-pyrophosphate (PYP) and 99m3,3di-phosphono-1, 2-

propanodicarboxylic acid (DPD) may be useful for identifying

ATTR amyloidosis

MYOCARDIUM AT MICROSCOPY

MYOCARDIUM UNDER POLARIZING MICROSCOPY

TREATMENTS OF PATIENTS WITH CARDIAC AL AMYLOIDOSIS AND OUTCOME

Grogan M, et al. Heart2017;103:1065–1072

CARDIAC SUPPORT THERAPIES

• Conventional medications: beta-blockers, angiotensin-converting

enzyme inhibitors and angiotensin receptor blockers, may contribute to

early mortality and worsening of symptoms 1

• Diuretics (loop diuretics and aldosterone receptor antagonists), in

addition to monitoring electrolytes and creatine, are predominant

supportive treatments 1

• LVAD → challenge: small LV cavities with thickened walls and coexisting

right ventricular dysfunction 2

• ICD have not been associated with survival benefit in patients with

cardiac AL amyloidosis in retrospective series 3

1…Grogan M, Dispenzieri A. Natural history and therapy of AL cardiac amyloidosis. Heart Fail Rev 2015;20:155–62.

2… Swiecicki PL et al. Left ventricular device implantation for advanced cardiac amyloidosis. J Heart Lung Transplant 2013;32:563–8.

3… Lin G, Dispenzieri A, Kyle R, et al. Implantable cardioverter defibrillators in patients with cardiac amyloidosis. J Cardiovasc

Electrophysiol 2013;24:793–8.

TREATMENT OF TTRA

TO RESUME

Diane Bodez: ESC congress Paris 2019