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SHORT REVIEWCARDIAC AMYLOIDOSIS
PresenterDr Praveen Gupta
Moderator Dr Ajith Ananthakrishna Pillai
Department of Cardiology PuducherryJIPMER (India)
Date: 01-11-2016
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Introduction Cardiac amyloidosis
Infiltrative cardiomyopathy
Amyloid proteinaceous material
Folded products of precursor proteins
Extracellular, nonbranching, 7 to 10 nm in diameter
Also contain serum amyloid P component, heparan and dermatan sulfate
proteoglycans and glycosaminoglycans, apolipoprotein E, type IV
collagen, and laminin
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Introduction Cardiac amyloidosis
Four Type defined by the precursor protein
Light chains from plasma cell dyscrasia (AL amyloidosis)
Wild-type transthyretin (TTR) (senile systemic amyloidosis )
Mutant TTR (familial ATTR amyloidosis)
Localized atrial amyloid from atrial natriuretic peptide
Secondary amyloidosis, from inflammatory protein serum amyloid A
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Introduction Cardiac amyloidosis
Clinical pattern and prognosis of cardiac amyloidosis differ among the
different types
AL has multiorgan manifestation
Familial affects the heart, the peripheral/ autonomic nervous system
SSA predominantly affects the heart
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Pathophysiology of cardiac amyloidosis*
*AL (Light-Chain) Cardiac AmyloidosisA Review of Diagnosis and TherapyRodney H. Falk, MDa; Kevin M.
Alexander, MDa; Ronglih Liao, PhDa; Sharmila Dorbala, MD, MPHa,b,J Am Coll Cardiol. 2016;68(12):1323
1341. doi:10.1016/j.jacc.2016.06.053
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AL Amyloidosis
Precursor protein is abnormal light chain
Produced by dysfunctional plasma cells.
Affects most organs, except central nervous system
50% cardiac
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AL Amyloidosis
Rapidly progressive heart failure
Biventricular, right-sided signs frequently predominate
Prominent peripheral edema and ascites
Angina because of amyloid infiltration into small vessels
Postural syncope due to autonomic dysfunction
Exertional syncope indicate fixed, low cardiac output (Severe)
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AL Amyloidosis Physical examination
Sinus rhythm or, atrial fibrillation
Normal- to low-volume pulse
Jugular venous pressure markedly elevated
Kussmaul sign is frequently present
Apex beat impalpable and heart sounds normal
Soft first heart sound if a first-degree atrioventricular (AV) block
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AL Amyloidosis Physical examination
Absence of fourth heart sound despite small
stiff ventricle (AL)
Atrial systolic dysfunction secondary to atrial
infiltration
Third heart sound indicates RV dysfunction
A pleural effusion, large (pleural amyloid)
Congested hepatomegaly & ascites
Noncardiac involvement periorbital purpura
(virtually pathognomonic of AL amyloidosis),
heavy proteinuria, peripheral or autonomic
neuropathy, macroglossia, or cachexia
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ECG
Low-voltage limb
leads, often with an
unusually rightward
axis
First-degree AV block
Q waves in V1 to V3
Left bundle branch
block is rare in AL
amyloidosis
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Normal to small LV cavity size
Increased LV and RV wall thickness
Increased myocardial echogenicity
Echocardiogram in a patient with AL amyloidosis: Parasternal (left) and apical four-chamber (right) views. Concentric wall thickening and biatrial enlargement with a pericardial effusion are evident. The patient was in severe heart failure and received a heart transplant followed by chemotherapy and autologous stem cell transplantation.
Mitral regurgitation(moderate)
Aortic valve seldom amyloidrelated dysfunction
Doppler tissue imaging-Elevated LV filling
pressure and severely impaired longitudinal LV
systolic function
Echocardiography
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Echocardiography
Speckle tracking shows -
Regional longitudinal
dysfunction
Apical sparing and
prolonged diastolic
relaxation
Asymmetric septal
thickening with LV outflow
tract gradient mimic HCM
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Cardiac catheterization
Bilateral elevation of filling
pressures
Dip-and-plateau tracing
LV and RV pressures during
respiration demonstrates
concordant changes in systolic
pressures
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Cardiac MRI
Useful diagnostic tool
Biventricular thickening with
normal cavity size
Atrial septal thickening
Delayed gadolinium
enhancement shows diffuse or
patchy subendocardial
enhancement
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Nuclear imaging
Negative for ischemia, even in a patient with angina
Positron emission tomography (PET) with vasodilator stress show
widespread stress-induced subendocardial ischemia related to the small-
vessel disease
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Familial and Senile Systemic Amyloidosis
Autosomal dominant disease with high penetrance
Due to a point mutation in hepatically expressed protein TTR (transports
thyroxine and retinol)
TTR is 55-kDa protein,serves as a carrier of the thyroid hormone thyroxine
(T4) and retinol binding protein bound to retinol
Two most common mutations are Val30Met and Val122Ile
Younger patients manifested as a neuropathy (Val30Met)
Cardiac involvement, if it occurs, consists of sinus node dysfunction and mild
cardiac infiltration (Val30Met)
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Familial and Senile Systemic Amyloidosis
Middle age, cardiomyopathy predominate (Val30Met)
Val122Ile results in cardiomyopathy in the sixth and seventh decades
Diagnosis missed unless molecular genetic testing undertaken(Val122Ile)
Never associated with neuropathy, other than carpal tunnel syndrome
(Val122Ile)
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Senile Systemic Amyloidosis
Wild-type TTR causes SSA
Although the term “systemic” is used, heart is the only organ involved
Occur from seventh decade onward
Predominantly men, with a male-to-female ratio 20 :1
Extensive deposits leading to cardiac dysfunction
Progressive biventricular failure with no associated neuropathy
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Familial and Senile Systemic Amyloidosis
In contrast to the low voltage of AL amyloidosis, the ECG in TTR
amyloidosis shows normal voltage with nonspecific conduction
disturbance and ST-T wave changes
Left bundle branch block is more common
SSA, high-degree AV block
Echocardiographic appearance similar to AL amyloidosis
Course is indolent
Untreated, survival is longer
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Familial and Senile Systemic Amyloidosis
Small-vessel disease less in TTR amyloidosis than in AL amyloidosis
Because of age, unrelated concomitant coronary artery disease present
Technetium pyrophosphate scanning for TTR amyloidosis is helpful
Strongly positive scan is pathognomonic for TTR amyloidosis
AL amyloidosis having little or no uptake of the isotope in myocardium
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Isolated atrial amyloid
Cannot be diagnosed other than biopsy
Predominant manifestation is an increased prevalence of atrial fibrillation
Not associated with ventricular amyloidosis
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Diagnosis
Relies on clinical awareness and suspicion for the disease, clinical features, blood and
tissue analysis, and positive findings on biopsy
In AL amyloidosis, serum and/ or urine immunofixation - monoclonal gammopathy
Excess of either kappa or lambda in greater than 90% of cases of AL amyloidosis
TTR amyloidosis- No monoclonal gammopathy & normal serum free light chain ratio
Unrelated monoclonal gammopathy of unknown significance in >5% of patients with
TTR amyloidosis
Bone marrow biopsy in AL amyloidosis, excess of plasma cells (10% to 20%)
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Diagnosis
Definitive diagnosis requires biopsy
Subcutaneous fat pad aspiration show amyloid deposits >80%
Yield of fat pad biopsy is lower in the TTR amyloidoses
Endomyocardial biopsy is universally positive
Endomyocardial biopsy low complication rate
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Diagnosis
Precise typing of the amyloid
Immunohistochemisty-Moderate specificity
Molecular analysis needed if clinical pattern is equivocal
Laser microdissection of amyloid deposits with subsequent proteomic
analysis is now considered the “gold standard
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Approach to a patient with suspected cardiac amyloidosis
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Treatment
The aim of treatment is twofold:
Treatment of the heart failure
Management of the underlying amyloidogenic protein
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Treatment of the heart failure
In AL amyloidosis, diuretics are the mainstay of therapy
Hypotension frequent (Autonomic dysfunction & low cardiac output)
ACE inhibitors, poorly tolerated
ACE inhibitors, precipitate worsening hypotension
Beta blockade for control of ventricular rate in atrial fibrillation
Calcium channel blockers contraindicated, as they worsen heart failure
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Treatment of heart failure
For severe heart failure, an intravenous infusion of diuretics with renal-
dose dopamine may help mobilize fluid
Inotropes are rarely helpful given the small cavity size
TTR amyloidosis without autonomic neuropathy, ACE inhibitors better
tolerated
If high-degree AV block , do biventricular pacing because RV pacing in
the stiff small-cavity ventricle appears to be particularly detrimental
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Treatment of amyloidogneic protein
Treatment of the plasma cell dyscrasia causing AL amyloidosis
Chemotherapy directed against plasma cells
High-dose chemotherapy with autologous stem cell transplantation
Bortezomib-based regimens rapidly controlling the underlying plasma
cell dyscrasia and stabilizing the patient
Long-term survival common
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Treatment
In familial ATTR amyloidosis requires liver transplantation
A combined liver-heart transplant considered in patients, particularly if
neuropathy and cardiomyopathy coexist
ATTR patients with a pure amyloid cardiomyopathy benefit from isolated
heart transplantation given the slow progressive nature of the disease
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Treatment
Heart transplantation for AL amyloidosis for patient with isolated cardiac
amyloidosis who also willing to undergo intensive chemotherapy for
plasma cell dyscrasia
SSA are outside the usual age range for cardiac transplantation, it has been
performed with a outcome
SSA is wild type, no role for liver transplantation
ICD limited to patients with aborted sudden death or syncope clearly
caused by a ventricular arrhythmia
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Efficacy of Chemotherapy for Light-Chain Amyloidosis in Patients Presenting With Symptomatic Heart Failure*
Three-drug therapy with bortezomib, dexamethasone, and an alkylating agent (BDex+AA) is associated with improved biomarker response rates in AL cardiac amyloidosis
To evaluate BDex+AA on mortality in AL cardiac amyloidosis Patients New York Heart Association (NYHA) functional class ≥II heart failure Retrospectively studied 106 patients ,40 received the 3-drug regimen, 66 received other regimens. Mortality 65% overall, 48% in BDex+AA cohort (median survival time 821 days), and
76% in patients who received other regimens (median survival time 223 days) BDex+AA was associated with decreased mortality (hazard ratio: 0.209; 95% confidence
interval: 0.069 to 0.636; p = 0.006) Use of BDex+AA in the treatment of AL amyloidosis is associated with improved survival
Recent advances
*J Am Coll Cardiol. 2016;67(25):2941-2948. doi:10.1016/j.jacc.2016.03.593
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Efficacy of Chemotherapy for Light-Chain Amyloidosis in Patients Presenting With Symptomatic Heart Failure*
*Brett W. Sperry, MD; Asad Ikram, MD; Rory Hachamovitch, MD; Jason Valent, MD; Michael N. Vranian, MD; Dermot Phelan, MD, PhD; Mazen Hanna, MD J Am Coll Cardiol. 2016;67(25):2941-2948. doi:10.1016/j.jacc.2016.03.593
Recent advances
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Non biopsy Diagnosis of Cardiac Transthyretin Amyloidosis*
Technetium-labeled bone scintigraphy tracers localize cardiac ATTR amyloidosis
Multicenter study
To ascertain diagnostic value of bone scintigraphy
1217 pts with suspected cardiac amyloidosis
Bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid
Grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a
monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac
ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0–100)
Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably
without the need for histology in patients who do not have a monoclonal gammopathy
Recent advances
*Circulation 2016 Jun 14;133(24):2404-12. doi: 10.1161/CIRCULATIONAHA.116.021612. Epub 2016 Apr 22
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Emerging Therapies for Transthyretin Cardiac Amyloidosis Could Herald a New Era for the Treatment of HFPEF*
*http://www.acc.org/latestincardiology/articles/2015/10/13/08/35/emergingtherapiesfortransthyretincardiacamyloidosis
Recent advances
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Emerging Therapies for Transthyretin Cardiac Amyloidosis Could Herald a New Era for the Treatment of HFPEF*
*http://www.acc.org/latestincardiology/articles/2015/10/13/08/35/emergingtherapiesfortransthyretincardiacamyloidosis
Recent advances
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Take home messaage Infiltrative cardiomyopathy
Four Type defined by the precursor protein
Light chains from plasma cell dyscrasia (AL amyloidosis) most common
Rapidly progressive heart failure
Bortezomib-based regimens rapidly controlling the underlying plasma
cell dyscrasia and stabilizing the patient
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Reference
Mann DL, Zipes DP, Libby P, Bonow RO. Braunwald's heart disease: a textbook of cardiovascular
medicine. Elsevier Health Sciences; 2014 Jul 30.
Sperry BW, Ikram A, Hachamovitch R, Valent J, Vranian MN, Phelan D, Hanna M. Efficacy of
chemotherapy for light-chain amyloidosis in patients presenting with symptomatic heart failure.
Journal of the American College of Cardiology. 2016 Jun 28;67(25):2941-8.
Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) Cardiac Amyloidosis: A Review of
Diagnosis and Therapy. Journal of the American College of Cardiology. 2016 Sep 20;68(12):1323-41
Emerging Therapies for Transthyretin Cardiac Amyloidosis Could Herald a New Era for the Treatment
of HFPEF Adam Castano, MD; David Narotsky, MD; Mathew S. Maurer, MD, FACC,
ExpertAnalysihttp://www.acc.org/latestincardiology/articles/2015/10/13/08/35/
emergingtherapiesfortransthyretincardiacamyloidosis
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