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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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