B P6 C53 Cardiac Amyloidosis

Question 1

The _____ are a group of diseases characterized by the extracellular deposition of insoluble, misfolded fibrillar proteins in the form of B-pleated sheets, resulting in organ dysfunction

Answer 1

Systemic amyloidoses

Question 2

The two most common types of amyloidosis that affect the heart are _____ amyloidosis.

Answer 2

Light chain (AL) amyloidosis and transthyretin (ATTR)

Question 3

Cardiac involvement can be demonstrated in up to ____% of cases of AL amyloidosis

Answer 3

70%

Question 4

Although most patients with AL amyloidosis do not have multiple myeloma, up to _____% of patients with multiple myeloma have coexisting AL amyloidosis.

Answer 4

10-15%

Question 5

In AL amyloidosis, a dysregulated plasma cell clone produces _____ immunoglobulin light chain fragments that have a propensity to misfold, aggregate, and deposit in the myocardial interstitium.

Answer 5

Kappa or lambda

Question 6

_____ light chain amyloidosis is more common than kappa, and organ systems affected include the heart, kidneys, liver, nervous system (including autonomic nervous system), gastrointestinal tract, and soft tissues.

Answer 6

Lambda

Question 7

Cardiac AL amyloidosis is viewed as a “toxic-infiltrative” cardiomyopathy involving two mechanisms:

Answer 7

(1) interstitial and/or perivascular amyloid fibril deposition leading to disruption of tissue architecture, microvascular dysfunction with angina/ischemia, and inhibition of contractile/relaxation functions

(2) direct toxicity to cardiomyocytes through, in part, p38 mitogen-activated protein kinase (MAPK) signaling

Question 8

Interstitial deposition results in a restrictive cardiomyopathy and heart failure, and direct cellular toxicity is thought to occur through induction of _____ in cardiomyocytes.

Answer 8

ROS and apoptosis

Question 9

_____, also known as prealbumin, is a tetrameric protein consisting of four identical subunits, synthesized in the liver, but also by the choroid plexus and retinal pigmented epithelial cells. TTR derives its name from its function as a circulating transporter of thy- roid hormone and retinol (vitamin A)

Answer 9

Transthyretin

Question 10

There are various impediments that hinder the recognition of car- diac amyloidosis by the cardiovascular clinician. First, the disease is generally perceived to be rare and presents with clinical and imag- ing features associated with more common conditions. Second, cardiac amyloidosis was, until recently, an untreatable disease with extremely poor prognosis lending credence to therapeutic nihilism. Third and finally,the diagnostic approach required endomyocardial biopsy,a procedure not appropriate in a scenario of low-pretest like- lihood or for widespread screening.

Question 11

Although differing by precursor protein, the final common patho-physiologic pathway of cardiac amyloidosis is one of myocardial infiltration and ______ that elicits symptoms of congestive heart failure.

Answer 11

Progressive impairment in diastolic and systolic function

Question 12

Left ventricular ejection fraction (LVEF) is preserved in early stages of the disease, while ______ is impaired.

Progressive infiltration and/or direct myocyte toxicity subsequently results in decrement in global left and right ventricular systolic function.

Answer 12

Longitudinal contraction

Question 13

The electrocardiogram (ECG) classically demonstrates a ____ in approximately 50% of patients with AL cardiac amyloidosis, while inferior or anterior pseudoinfarcts are seen in greater than 70% of AL cases.

Low voltage is seen in only 25% to 40% of patients with ATTR, while up to 15% can show evidence of left ventricular hypertrophy.

Answer 13

Low-voltage pattern

Question 14

This is more commonly ECG feature of ATTR amyloidosis.

Answer 14

Conduction disease progressing to heart block

Question 15

Atrial dysrhythmias, particular ____, are seen in up to 40% to 60% of patients with wtATTR amyloidosis at diagnosis and in up to 90% over time.

The risk of intracardiac thrombus is increased in all patients with cardiac amyloidosis, even those in sinus rhythm, with stroke or systemic embolization occurring in some patients

Answer 15

Atrial fibrillation (AF) and flutter

Question 16

Although a low-voltage pattern itself can be attributable to other causes (pericardial effusion, lung hyper-expansion), integration of ____ seen by echocardiography in the setting of a low-voltage pattern (the mass to voltage ratio), increases diagnostic accuracy.

Answer 16

Increased wall thickness

Question 17

Clinical features of AL amyloidosis are myriad and follow organ system infiltration including renal (proteinuria, often nephrotic range), soft tissue (_____, _____), gastrointestinal (bleeding), or neurologic (_____).

Answer 17

Soft tissue: macroglossia, carpal tunnel syndrome

Neurologic: peripheral or autonomic neuropathy

Question 18

____ resulting from capillary fragility is considered a pathognomonic feature of AL amyloidosis and is not seen in ATTR amyloidosis

Carpal tunnel syndrome, lumbar spinal stenosis (ligamentum flavum thickening), and spontaneous tendon ruptures (biceps in particular) are seen in ____

Answer 18

Periorbital ecchymosis

Wild type ATTR - bicep tendon rupture

Question 19

For example, the pVal50Met variant causes predominantly neuropathy in early-onset disease (third or fourth decade) but cardiomyopathy and neuropathy in later onset (sixth or seventh decade of life).

The pThr80Ala variant causes either cardiomyopathy or neuropathy,or both,with onset in the fifth decade.

Answer 19

pVal50Met
Early neuropathy
Late CMP and Neuropathy

pThr80Ala
CMP, Neuropathy at 5th decade

Question 20

The critical step to enable a diagnosis of cardiac amyloidosis is _____ forged, in part, by attention to associated signs/symptoms and reassessment of changes in clinical features previously attributed to other processes.

Answer 20

Clinical suspicion

Question 21

In addition, several “red flag” features have been proposed including extreme

Answer 21

Left ventricle (LV) wall thickening (>15 mm)
Discordant ECG voltage as predicted from wall thickness
Orthopedic/soft tissue manifestations
Characteristic patterns on imaging testing

Question 22

Diagnosis of amyloidosis classically requires tissue biopsy with ____ and precursor protein identification by immunohistochemistry and/or mass spectrometry.

Answer 22

Congo red (or Thioflavin) staining

Question 23

In the case of AL amyloidosis, a _____ is required to establish the diagnosis. Establishment of cardiac amyloidosis, however, does not require an endomyocardial biopsy, as supportive evidence from imaging and biomarker testing afford a very high predictive value for cardiac involvement.

Answer 23

Tissue biopsy

Question 24

Furthermore, it is the ____ in AL that defines treatment regimens, rather than the binary adjudication of cardiac involvement

Answer 24

Severity of cardiac impairment

Question 25

Unlike AL, ATTR amyloidosis can now be accurately diagnosed with imaging testing (nuclear scintigraphy) combined with testing for light chain amyloidosis, when performed in the proper clinical context.

Give the tracers:

Answer 25

PYP, DPD, or HMDP

Question 25

These are biochemical hallmark features of cardiac amyloidosis but are nonspecific.

Answer 25

Persistent and unexplained elevation in cardiac biomarkers - troponin, natriuiretic peptides

Question 26

In AL, abnormal increase in either ____ (more common) or kappa free light chain with abnormal ratio, and/or identification of a monoclonal band on immunofixation electrophoresis is indicative of a plasma cell dyscrasia.

Answer 26

Lambda

Question 27

In addition, MGUS incidence increases with age and plasma cell testing abnormalities can be seen in up to 40% to 50% of patients with ATTR amyloidosis.

Thus hemato- logic consultation is indispensable in unclear scenarios.

A ____ is insensitive for identifying AL amyloidosis and should not be obtained without subsequent immunofixation.

Answer 27

Serum protein electrophoresis (SPEP)

Question 28

Echocardiography is indispensable. Findings include increased ____ (above the upper limit of normal for age and sex but often 12 mm for the LV), ______, interatrial septal thickening, valvular thickening, evidence of right ventricular thickening, pericardial effusion, dilated inferior vena cava, diastolic dysfunction, and increased left atrial pressures

Answer 28

Biventricular thickening

Dilated atria

Question 29

Global measures of systolic function are generally preserved in early to midstage disease; however, segmental variation in systolic function is evident early.

Global longitudinal strain is often reduced and in specific, _____. This distinctive pattern is described as “apical sparing” and can be quantified with longitudinal systolic strain deformational imaging with an approximate _____ or ______ (relative apical sparing).

_____ is also suggestive of amyloid cardiomyopathy

Answer 29

Basal segments often are hypokinetic relative to apical segments

Apical/basal ratio of greater than 2
Apical/basal+mid strain greater than 0.7

Increased LVEF/global longitudinal strain ratio greater than 4

Question 30

Cardiac amyloidosis demonstrates diffuse enhancement throughout the myocardial segments, either in a ______, often with atrial involvement.

The inability to suppress (“null”) the myocardium in cine-inversion recovery (Look-Locker) sequences is a common feature

Answer 30

Global subendocardial or transmural pattern

Question 31

LGE CMR is approximately 85% to 90% sensitive and specific for identification of amyloid cardiomyopathy in patients with clinically suspected disease

As extracellular amyloid fibril deposition increases, the interstitial space between myocytes expands. Parametric T1 mapping demonstrates increased native (noncontrast) T1 and ECV is typically greater than 0.40.

Question 32

Tracers (tracer uptake compared with RIB):
99mTc-pyrophosphate (PYP), 99mTc-3,3-diphosphono1,2-propanedicarboxylic acid (DPD)
99mTc-hydroxyl-methylenediphosphonate (HMDP)
-Grade 0 (no uptake) to grade 3 (cadiac uptake greater than rib) and determined either after 1 or 3 hours of tracer incubation

How can ATTR be differentiated with AL:

Answer 32

Usong 99mTc PYP (by a heart to contralateral lung (H/CL) quantitative uptake ratio of greater than 1.5 after a 1 hour of tracer incubation)

Nuclear tracers provided 100% specificity when grade 2 or 3 uptake was seen in the absence of a monoclonal protein by serum or urine in individuals with heart failure and typical echocardiographic or CMR features of amyloidosis.

Question 33

_____ remains the “gold standard” for diagnosis of car- diac amyloidosis and is considered 100% sensitive and specific if biopsy specimens are collected from multiple sites (four or more are recom- mended)

Answer 33

Endomyocardial biopsy

Question 34

Endomyocardial biopsy carries a small but notable risk of perforation, tamponade, or access site complications and as such is reserved for confirmatory testing in suspected cases wherein imaging testing is inconclusive (or isolated AL cardiac amyloidosis)

Question 35

_____ is a final critical step in the ATTR amyloidosis diagnostic algorithm because it has implications for treatment as well as raises the possibility of gene inheritance for first-degree relatives.

Answer 35

Genotyping of TTR

Question 36

This has been most widely explored for the pVal142Ile genotype. Although data clearly demonstrate that the inheritance of the pVal142Ile allele increases the risk of heart failure,7 evidence from other studies suggest that the allele does not necessarily result in imag- ing evidence of ATTR amyloidosis.

Question 37

Furthermore, a genotyping-only approach will fail to identify ATTRwt, the most common type of cardiac amyloidosis.

Question 38

Although bone avid radiotracers have been used for myocar- dial infarction imaging for more than 40 years, it is now recognized that the tracers ____ can detect cardiac amyloidosis and differentiate ATTR from AL

Answer 38

99mTc-pyrophosphate (PYP), 99mTc-3,3-diphosphono- 1,2-propanedicarboxylic acid (DPD), and 99mTc-hydroxyl-methylene- diphosphonate (HMDP)

Question 39

Alternatively, ATTR cardiac amyloidosis can be differentiated from AL using 99mTc PYP (the tracer available in United States) by a _____ a region of interest drawn over the heart and contralateral chest after a 1 hour of tracer incubation

Answer 39

Heart to contralateral lung (H/CL) quantitative uptake ratio of greater than 1.5 from

Question 40

Bioavailable ____ and ____ are the preferred first-line agents with frequent dose adjustments to address changes in volume status that may result from concomitant chemotherapies for AL amyloidosis, such as steroids.

Answer 40

Loop diuretics and aldosterone antagonists

Question 41

Bioavailable loop diuret- ics and aldosterone antagonists are the preferred first-line agents with frequent dose adjustments to address changes in volume status that may result from concomitant chemotherapies for AL amyloidosis, such as steroids.

Question 42

Patients with orthostasis from poor vascular tone owing to impaired autonomic function may require the alpha-agonist ___ to maintain adequate systolic blood pressure.

Answer 42

Midodrine

Question 43

Evidence-based therapies that have proven beneficial in other causes of heart failure including ____ are generally poorly tolerated in patients with advanced cardiac amyloidosis owing to fixed stroke volume and impaired hemodynamic compensatory mechanisms

Answer 43

ACE inhibitors, ARBs, ARNIs, and beta blockers

Question 44

This are generally contraindicated in cardiac amyloidosis because they can bind amyloid fibrils (demonstrated in AL only), and worsen heart failure through heart-rate slowing, negative inotropy, and potentiation of conduction block

Answer 44

Non-dihydropyridine calcium channel blockers (CCBs)

Question 45

_____ may be useful as adjunctive agents for blood pressure management, particularly in the context of renal dys- function, although potentiation of lower-extremity edema may limit application

Answer 45

Dihydropyridine CCBs

Question 46

Atrial dysrhythmias, particularly AF and atrial flutter, are extremely com- mon in ______ and less commonly seen in AL amyloidosis.

Management involves anticoagulation to prevent thromboembolism and rate control, and if exacerbating symptoms of heart failure, rhythm control is also appropriate.

Answer 46

AF - ATTR amyloidosis

Question 47

Maintaining sinus rhythm and the atrial contribution to ventricular filling in cardiac amyloidosis may be less important because many patients have significantly ______, reducing the atrial contribution to ventricular filling.

Answer 47

Reduced atrial mechanical function,

Question 48

The stroke risk among patients with AF and cardiac amyloidosis is exceedingly high because of blood stasis and elevated pressures, and ____ may potentiate thrombosis.

Answer 48

Atrial amyloid deposition

Question 49

____ has been observed in the context of normal sinus rhythm and after therapeutic anticoagulation, underscoring the imperative to perform transesophageal echocardiography prior to attempts at restoration of sinus rhythm by cardioversion

Answer 49

Left atrial appendage thrombosis

Question 50

Heparins, vitamin K antagonists, or direct-acting oral anticoagulants are all effective in reducing thromboembolic risk and should be considered as _____ with minimal interruption

Answer 50

Indefinite therapy

Question 51

As specified in recent American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/ AHA/HRS) recommendations, agents that may be used for rhythm control include

Answer 51

Rhythm control: Amiodarone (most commonly) and Dofetilide

Question 52

Data supporting the use of catheter ablation in cardiac amyloidosis are limited.

In early-stage patients, cavotricuspid isthmus ablation may help to main- tain sinus rhythm in the setting of atrial flutter, while _____ are generally less effective at controlling AF than in nonamyloid populations.

Answer 52

Pulmonary venous isolation procedures

Question 53

The routine use of automatic implantable cardioverter-defibrillators (ICDs) in patients with cardiac amyloidosis is debatable as sudden cardiac death related to ventricular tachycardia (VT) or ventricular fibrillation (VF) is relatively uncommon and mortality typically results from ____

Answer 53

Pulseless electrical activity

Question 54

The ultimate goal of chemotherapy for AL amyloidosis is ___ that produces the amyloidogenic light chain.

Arresting amyloid production reverses disease progression, preserves organ function, and enhances survival.

Answer 54

Elimination of the plasma cell clone

Question 55

The objective is attainment of a _____ defined as normalization of the involved free light chain and light chain ratio, elimination of a monoclonal band by immunofixation electrophoresis, and normalization of the bone marrow plasma cell population

Answer 55

Complete hematologic response (CR)

Question 56

First-line strategies in AL vary by institutional experience and must be individualized to a particular patient.

In appropriately selected patients managed at highly specialized referral centers with extensive experience, _____ can be applied as a means to rapidly reduce the light chain concentration

Answer 56

High-dose melphalan-based chemotherapy coupled with autol- ogous stem cell transplant (HDM/SCT)

Question 57

Eligibility for HDM/SCT is defined by various clinical parameters including (but not limited to) LVEF, pulmonary function, blood pressure, and per- formance status.

Question 58

In specific, a monoclonal antibody targeting the CD38-receptor (____), developed for the treatment of patients with relapsed multiple myeloma, has produced a rapid and profound hematologic response with minimal toxicity.

Answer 58

Daratumumab

Question 59

_______ is the first and only agent specifically approved by FDA for AL amyloidosis and is now considered first line therapy in combination with cytoxan, bortizimib, and dexamthasone.

Answer 59

Daratumumab

Question 60

Presently, there are three U.S. Food and Drug Administration (FDA)- approved therapies for ATTR amyloidosis including the TTR silencers _____,and the TTR stabilizer tafamidis,with additional novel agents in clinical trials.

In addition, the FDA-approved nonsteroidal antiinflammatory drug (NSAID) ____ has been repurposed for ATTR amyloidosis treatment and demonstrated efficacy in smaller, nonrandomized,retrospective studies.

Answer 60

Stabilizers: Tafamidis
Silencers: Patisiran and inotersen
NSAID: diflunisal

Question 61

This is the only therapeutic approved for ATTRwt cardiac amyloidosis.

Answer 61

Tafamidis