cardiac amyloidosis
TRANSCRIPT
Cardiac Amyloidosis
Magdy El-MasryProf. of Cardiology
Tanta University
Amyloid
Rudolph Virchow in 1854 adopted the term
“amyloid” to refer to tissue deposits of
material that stained in a similar manner to
cellulose when exposed to iodin
Amyloid has blue staining with iodine .
(Virchow 1854)
Cellulose (amylum) has the same staining.
(a) H and E stain showing extensive amyloid infiltration of the myocardium (lightpink) which distorts and separates the myocytes (darker pink).
(b) Staining with Sulfated Alcian Blue (another patient) shows typical amyloid staining with turquoise staining of the amyloidand yellow myocyte staining.
The amyloidoses are a diverse group of disorders whose effects are felt in every part of the body and every corner of the globe.
The hallmark of these diseases is the aggregation and deposition of misfolded protein as insoluble amyloid fibrils.
AmyloidosisA protein misfolding disease
The two most common forms of cardiac amyloidosis are the AL and ATTR types.
Pathogenetic steps in the development of amyloid diseases.
Inherited mutations in transthyretin cardiac amyloidosis (ATTR) or the aging process in wild-type disease (ATTRwt) cause destabilization of the transthyretin (TTR) protein into monomers or oligomers, which aggregate into amyloid fibrils. These insoluble fibrils accumulate in the myocardium and result in diastolic dysfunction, restrictive cardiomyopathy, and eventual congestive heart failure
Pathogenetic steps in the development of amyloid diseases.
AL amyloidosis A : Amyloid fibril protein >>> derived from immunoglobulin light (L) chains
ATTR amyloidosisA : Amyloid fibril protein >>> derived from the plasma protein transthyretin ( TTR )
ATTRwt amyloidosisWild-type ATTR
ATTR V30M amyloidosisWhere the normal valine residue at position 30 has been substituted with methionine.
Some types of amyloid have a greater predilectionfor the heart than others.
The two most common forms of cardiac amyloidosis are the AL and ATTR types. AL amyloidosis may involve almost any other organ in the body, whereas inherited ATTR amyloidosis variably involves the heart and autonomic and peripheral nerves.
Nonhereditary ATTR amyloidosis has almost exclusively a cardiac phenotype.
The commonly diagnosed types of cardiac amyloidosis
The commonly diagnosed types of cardiac amyloidosis
Primary (AL) ATTRwt (Senile CA)
ATTR V122I ATTR T60A ATTR V30M
Precursor/amyloidogenicprotein
MonoclonalImmuno-globulinlight chain
Wild-typetransthyretin
Varianttransthyretin
Varianttransthyretin
Varianttransthyretin
Average age atpresentation
60–70 years 70–80 years ≥60 years ≥60 years 30–40 or 50–60years
Commonethnicity
Any Caucasian African/Caribbean
Caucasian(Irish
Any (Portuguese,Swedish,Japanese
Primary (AL) ATTRwt (Senile CA)
ATTR V122I ATTR T60A ATTR V30M
Frequency ofcardiacinvolvement
40–50% Almost 100% Almost 100% Detectable in at least 90%
Uncommon
Other systemicinvolvement
Kidney, liver, softtissue, nerves,spleen
Carpal tunnel(bladder, spine)
Carpal tunnel
Nerves Nerves
The commonly diagnosed types of cardiac amyloidosis
AL, monoclonal immunoglobulin light chain amyloidosis; ATTR, transthyretin amyloidosis; ATTRwt; transthyretin amyloidosis associated with wild-type transthyretin; SCA, senile cardiac amyloidosis
AMYLOIDOSIS
Rare, Underserved, and Underdiagnosed
Famous People with Amyloidosis
A constant complaint of patients with rare diseases is the long delay between the first symptom and the clinical diagnosis made by physicians.
This is also true for amyloidosis and can be explained in part by the great number of organs and systems that can be affected by amyloid deposits leading to a large variety of symptoms, none of them being specific of the disease.
Virtually all organs can be affected by amyloidosis.
Clinical DiagnosisAmyloidosis as a Great Masquerader
Potential for misdiagnosis: physician- and disease related factors
Cardiac amyloidosis is often misdiagnosed as anothercondition or delayed in its recognition as a result of
bothphysician-related and
disease-related reasons
Factors leading to misdiagnosis
Fragmented knowledge among different specialties and subspecialties
Shortage of centres and experts dedicated to specialised disease management
Erroneous belief it is an untreatable disease
Physician-related factors
Factors leading to misdiagnosis
Common misconceptions about diagnosing and typing amyloid
• Low voltage is not sensitive nor specific finding in isolation to exclude the presence of CA• Serum protein electrophoresis is not a sufficient screening test to exclude the presence of a plasma cell disorder that can cause AL amyloid • A fat pad biopsy has a sensitivity for AL amyloid of 70 % at best and is positive in<50 % of subjects with ATTR CA
Physician-related factors
Factors leading to misdiagnosisDisease-related factors
Rarity
Intrinsic phenotypic heterogeneity
Genotypic heterogeneity in ATTR
Necessity of target organ tissue histological diagnosis in the vast majority of cases
Main known determinants of phenotypic heterogeneity in ATTR.
Genotype–phenotype correlation in ATTR.
Some mutations are associated with both neurological and cardiac manifestations, whereas others lead to an exclusively neurological disease and a small number are associated with an exclusively cardiological phenotype.
Caveats and pearls in cardiac amyloidosis • A definite diagnosis of cardiac amyloidosis requires
not only tissue biopsy proof of amyloidotic infiltration but also the identification of the precursor protein causing amyloid (since treatment strictly depends upon aetiology)
• A high index of suspicion is mandatory for the recognition of CA in the clinical arena (e.g. if you don’t think of it, you won’t diagnose it!)
Caveats and pearls in cardiac amyloidosis
• Cardiac amyloid should be suspected in any patient with heart failure, unexplained increased LV wall thickness and non-dilated LV
• In a patient with an initial diagnosis of HCM, look for the infiltrative phenotype hidden beneath the hypertrophic one!
Caveats and pearls in cardiac amyloidosis
• A distinctive sign of CA is the abnormal ratio between LV thickness and QRS voltages rather than low QRS voltages alone.
The absence of low QRS voltages does not rule out a CA if the context is otherwise fitting and up to 20 % of subjects with CA can have ECG evidence of LV hypertrophy
Caveats and pearls in cardiac amyloidosis
• In an elderly man with unexplained concentric LV hypertrophy, especially in the absence of hypertension, always consider the possibility of wild-type TTR CA!
• CA in an elderly patient with monoclonal gammopathy is not necessarily related to AL: consider the possibility of wild-type TTR +MGUS (monoclonal gammopathy of uncertain significance)
Caveats and pearls in cardiac amyloidosis
• Longitudinal LV function can be severely depressed despite a normal LV ejection fraction and the myocardial contraction fraction are often low suggesting reduced global myocardial shortening
• Myocardial deformation is reduced in CA, but the apex is generally spared
Caveats and pearls in cardiac amyloidosis
• In CA, LGE (late Gd enhancement ) distribution at MRI is heterogeneous: subendocardial LGE is not the only diagnostic pattern and the absence of LGE does not exclude CA
• Bilateral carpal tunnel syndrome in a man with HCM-like phenotype on echo is highly suggestive of TTR-related CA
Evaluation to Diagnose
ATTR
Diagnostic pathway to arrive at a diagnosis of ATTR
Diagnostic pathway to arrive at a diagnosis of ATTR
Emerging Therapies for Transthyretin Cardiac Amyloidosis
Emerging Therapies for Transthyretin Cardiac Amyloidosis
ReferencesRapezzi C et al . Cardiac amyloidosis: the great pretender. Heart Fail Rev 2015; 20:117–124
Patel K S & Hawkins P N . Cardiac amyloidosis: where are we today?. J Intern Med 2015; 278: 126–144.
Castano A et al. Emerging Therapies for Transthyretin Cardiac Amyloidosis Could Herald a New Era for the Treatment of HFPEF. http://www.acc.org/latest-in-cardiology/articles/2015/10/13/08/35/emerging-therapies-for-transthyretin-cardiac-amyloidosis
Gertz M A et al . Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J Am Coll Cardiol. 2015;66(21):2451-2466