II. Epidemiology
- Underrecognized as a cause of Heart Failure with Preserved Ejection Fraction (HFpEF)
- May represent up to 13% of HFpEF cases admitted to the hospital
- González-López E (2015) Eur Heart J 36(38):2585-94 +PMID: 26224076 [PubMed]
III. Pathophysiology
- Progressive, infiltrative disease of cardiac Muscle via misfolded amyloid Protein fibril deposition
- Results in progressive thickening of ventricular walls, with secondary Restrictive Cardiomyopathy
- Amyloid also deposits in other tissues
- Nerve deposition causing Peripheral Neuropathy, Autonomic Dysfunction (and Orthostatic Hypotension), and Erectile Dysfunction
- Tendon deposition resulting in Biceps Tendon Rupture and bilateral Carpal Tunnel Syndrome (esp. older patients)
- Musculoskeletal symptoms may precede cardiovascular manifestations by 7 years
- More than 30 amyloid subtypes exist (9 affect heart), but 2 types predominate (98%) in Cardiac Amyloidosis
- Monoclonal Immunoglobulin Light Chains (AL)
- Monoclonal Gammopathy (Hematologic Malignancy)
- Associated with high mortality in first year without prompt diagnosis and treatment
- Transthyretin or TTR transport Protein (ATTR)
- Acquired or Wild-Type (ATTRwt)
- Hereditary or Variant (ATTRv)
- Amyloidogenic V142I variant of the transthyretin (TTR) affects up to 4% of those with West African heritage
- Monoclonal Immunoglobulin Light Chains (AL)
IV. Indications: Screening
- Left Ventricular Wall Thickness >=12 mm AND
- At least 1 red flag or clinical scenario
- Heart Failure in age >=65 years
- Aortic Stenosis >=65 years
- Previously hypertensive, but now normotensive or hypotensive
- Autonomic Dysfunction or sensory involvement
- Peripheral Polyneuropathy
- Proteinuria
- Skin Bruising
- Bilateral Carpal Tunnel Syndrome
- Ruptured biceps tendon
- Cardiac MRI with subendocardial or transmural Late Gadolinium Enhancement (LGE) or increased extracellular volume (ECV)
- Reduced longitudinal strain with apical sparing
- Decreased QRS voltage to mass ratio
- Pseudo Q Waves on EKG
- AV conduction disease
- Possible Family History of Amyloidosis
V. Imaging: Bone Scan
- Diphosphate Scintigraphy (Tc99-DPD/PYP/HMDP with SPECT)
- Primarily indicated in ATTR type Amyloidosis
- Grading of increased cardiac uptake (Grade 2 or 3 should raise suspicion for Cardiac Amyloidosis)
- Grade 0: Myocardial uptake ABSENT, and bone uptake normal
- Grade 1: Myocardial uptake LOWER than bone uptake
- Grade 2: Myocardial uptake SIMILAR to bone uptake
- Grade 3: Myocardial uptake GREATER than bone, and reduced bone uptake
VI. Imaging: Echo Criteria for Cardiac Amyloidosis
- Unexplained left ventricular (LV) thickness >=12 mm AND
- One of the 2 echo criteria sets positive
- Echo with >=2 of the following
- Grade 2 or worse Diastolic Dysfunction
- Reduced tissue doppler s', e' and a' wave velocities (<5 cm/s)
- Decreased global longitudinal LV strain (absolute value <-15%)
- Mutiparametric echo score >=8 points (total cummulative points)
- Score 3: Relative LV Wall Thickness (IVS+PWT)/LVEDD >0.6
- Score 1: Doppler E wave/e' wave velocity >11
- Score 2: TAPSE <=19 mm
- Score 1: LV global longitudinal strain absolute value <= -13%
- Score 3: Systolic longitudinal strain apex to base ratio >2.9
- Echo with >=2 of the following
VII. Imaging: Cardiac MRI Criteria for Cardiac Amyloidosis
- Indicated when type of Cardiomyopathy is unclear
- Findings
- Diffuse subendocardial or transmural Late Gadolinium Enhancement (LGE, required for diagnosis)
- Abnormal gadolinium kinetics with myocardial nulling preceding or coinciding with blood pool (required for diagnosis)
- Increased extracellular volume (ECV) >=0.40% (supportive, but not diagnostic, and not required for diagnosis)
VIII. Labs
- Serum and Urine immunofixation (SPIE, UPIE)
- Most important first test in suspected Cardiac Amyloidosis (to identify AL Type)
- Detects monoclonal Protein (clonal Ig or light chains)
- Normal in ATTR type of Cardiac Amyloidosis
- Positive in AL Type and should prompt urgent hematology referral and biopsy
- Serum free light chains
- Measures ratio of Serum K+appa to lambda light chains
- Detects Detecting low-level clonal light chain production
- Normal range varies by assay, but a ratio far from 1:1 may suggest clonal production
- Normal in ATTR type of Cardiac Amyloidosis (abnormal ratio in AL type)
- Other findings
- NT-proBNP elevated out of porportion to degree of Heart Failure
- Serum Troponin persistently elevated (despite non-occlusive Coronary Vessels)
- Renal Insufficiency and Proteinuria may be present in some types of Amyloidosis (including AL)
IX. Diagnosis
- Step 1: Initial, Noninvasive Tests (sufficient alone for ATTR type diagnosis)
- Echocardiogram criteria as above (obtain in all suspected cases) AND
- Serum Markers (obtain in all suspected cases to exclude AL type)
- Positive results suggest AL type (which requires urgent biopsy for diagnosis)
- Serum free light chains negative in ATTR
- Serum and Urine immunofixation (SPIE, UPIE) negative in ATTR
- Other imaging to confirm ATTR diagnosis (sufficient without biopsy)
- Diphosphate Scintigraphy (Tc99-DPD/PYP/HMDP with SPECT) with increased cardiac uptake (Grade 2 or 3)
- Cardiac MRI (see imaging)
- Step 2: Invasive Tests if nondiagnostic initial tests (and biopsy is required for AL type diagnosis)
- Cardiac biopsy positive for amyloid OR
- Extracardiac biopsy positive for amyloid AND echo and Cardiac MRI consistent with amyloid
X. Management: General and Secondary Associated Conditions
-
Aortic Stenosis
- Associated with worse prognosis
- Consider TAVR
-
Heart Failure
- Treat with Diuretics and fluid control
- Avoid Beta Blockers and ACE/ARBs
- LVAD is not indicated in most patients
- Consider Heart Transplant
-
Atrial Fibrillation
- Amiodarone is the preferred Antiarrhythmic in Cardiac Amyloidosis
- Exercise caution with Digoxin
- Risk of complications with electrical cardioversion
- Atrial Fibrillation often recurrs after cardioversion
- Obtain TEE echo before cardioversion to exclude cardiac thrombus
-
Thromboembolism
- Increased risk in Amyloidosis
- Anticoagulation for Atrial Fibrillation (regardless of CHADS-VASC)
- Conduction Disorders
- Pacemaker indications are the same as without Amyloidosis
- Ventricular Arrhythmia
- Transvenous Implantable Cardioverter-Defibrillator
- Indicated for secondary prevention of ventricular Arrhythmia (not primary)
- Transvenous Implantable Cardioverter-Defibrillator
-
Neuropathy
- Refer to neurology
- Genetic Silencers may be considered
XI. Management: Amyloidosis Specific
- Light-chain Amyloidosis (AL)
- Urgent referral for biopsy
- Treated as a Hematologic Malignancy (Monoclonal Gammopathy)
- Transthyretin Amyloidosis (ATTR)
- Synthesis suppression
- Liver Transplant
- Genetic Editing
- Genetic Silencers (e.g. Inotersan)
- TTR Stabilization
- Diflunisal
- Tafamidis or Acoramidis
- Elimination of amyloid deposits
- Doxycycline
- Antibodies (PRX004, NI006)
- Epigallocatechin gallate (EGCG) in Green Tea
- Synthesis suppression
XII. Resources
- Cardiac Amyloidosis (Curbsiders)