B P6 C53 Cardiac Amyloidosis Flashcards
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
Systemic amyloidoses
The two most common types of amyloidosis that affect the heart are _____ amyloidosis.
Light chain (AL) amyloidosis and transthyretin (ATTR)
Cardiac involvement can be demonstrated in up to ____% of cases of AL amyloidosis
70%
Although most patients with AL amyloidosis do not have multiple myeloma, up to _____% of patients with multiple myeloma have coexisting AL amyloidosis.
10-15%
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.
Kappa or lambda
_____ 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.
Lambda
Cardiac AL amyloidosis is viewed as a “toxic-infiltrative” cardiomyopathy involving two mechanisms:
(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
Interstitial deposition results in a restrictive cardiomyopathy and heart failure, and direct cellular toxicity is thought to occur through induction of _____ in cardiomyocytes.
ROS and apoptosis
_____, 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)
Transthyretin
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.
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.
Progressive impairment in diastolic and systolic function
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.
Longitudinal contraction
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.
Low-voltage pattern
This is more commonly ECG feature of ATTR amyloidosis.
Conduction disease progressing to heart block
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
Atrial fibrillation (AF) and flutter
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.
Increased wall thickness
Clinical features of AL amyloidosis are myriad and follow organ system infiltration including renal (proteinuria, often nephrotic range), soft tissue (_____, _____), gastrointestinal (bleeding), or neurologic (_____).
Soft tissue: macroglossia, carpal tunnel syndrome
Neurologic: peripheral or autonomic neuropathy
____ 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 ____
Periorbital ecchymosis
Wild type ATTR - bicep tendon rupture
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.
pVal50Met
Early neuropathy
Late CMP and Neuropathy
pThr80Ala
CMP, Neuropathy at 5th decade
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.
Clinical suspicion
In addition, several “red flag” features have been proposed including extreme
Left ventricle (LV) wall thickening (>15 mm)
Discordant ECG voltage as predicted from wall thickness
Orthopedic/soft tissue manifestations
Characteristic patterns on imaging testing
Diagnosis of amyloidosis classically requires tissue biopsy with ____ and precursor protein identification by immunohistochemistry and/or mass spectrometry.
Congo red (or Thioflavin) staining
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.
Tissue biopsy
Furthermore, it is the ____ in AL that defines treatment regimens, rather than the binary adjudication of cardiac involvement
Severity of cardiac impairment
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:
PYP, DPD, or HMDP
These are biochemical hallmark features of cardiac amyloidosis but are nonspecific.
Persistent and unexplained elevation in cardiac biomarkers - troponin, natriuiretic peptides
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.
Lambda
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.
Serum protein electrophoresis (SPEP)
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
Biventricular thickening
Dilated atria
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
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
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
Global subendocardial or transmural pattern
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.
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:
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.
_____ 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)
Endomyocardial biopsy
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)
_____ 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.
Genotyping of TTR
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.
Furthermore, a genotyping-only approach will fail to identify ATTRwt, the most common type of cardiac amyloidosis.
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
99mTc-pyrophosphate (PYP), 99mTc-3,3-diphosphono- 1,2-propanedicarboxylic acid (DPD), and 99mTc-hydroxyl-methylene- diphosphonate (HMDP)
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
Heart to contralateral lung (H/CL) quantitative uptake ratio of greater than 1.5 from
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.
Loop diuretics and aldosterone antagonists
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.
Patients with orthostasis from poor vascular tone owing to impaired autonomic function may require the alpha-agonist ___ to maintain adequate systolic blood pressure.
Midodrine
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
ACE inhibitors, ARBs, ARNIs, and beta blockers
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
Non-dihydropyridine calcium channel blockers (CCBs)
_____ 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
Dihydropyridine CCBs
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.
AF - ATTR amyloidosis
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.
Reduced atrial mechanical function,
The stroke risk among patients with AF and cardiac amyloidosis is exceedingly high because of blood stasis and elevated pressures, and ____ may potentiate thrombosis.
Atrial amyloid deposition
____ 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
Left atrial appendage thrombosis
Heparins, vitamin K antagonists, or direct-acting oral anticoagulants are all effective in reducing thromboembolic risk and should be considered as _____ with minimal interruption
Indefinite therapy
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
Rhythm control: Amiodarone (most commonly) and Dofetilide
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.
Pulmonary venous isolation procedures
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 ____
Pulseless electrical activity
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.
Elimination of the plasma cell clone
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
Complete hematologic response (CR)
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
High-dose melphalan-based chemotherapy coupled with autol- ogous stem cell transplant (HDM/SCT)
Eligibility for HDM/SCT is defined by various clinical parameters including (but not limited to) LVEF, pulmonary function, blood pressure, and per- formance status.
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.
Daratumumab
_______ 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.
Daratumumab
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.
Stabilizers: Tafamidis
Silencers: Patisiran and inotersen
NSAID: diflunisal
This is the only therapeutic approved for ATTRwt cardiac amyloidosis.
Tafamidis
