Cardiac Amyloidosis

Aka: Cardiac Amyloidosis, Amyloid Cardiomyopathy

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II. Epidemiology

  1. Underrecognized as a cause of Heart Failure with Preserved Ejection Fraction (HFpEF)
    1. May represent up to 13% of HFpEF cases admitted to the hospital
    2. González-López E (2015) Eur Heart J 36(38):2585-94 +PMID: 26224076 [PubMed]

III. Pathophysiology

  1. Progressive, infiltrative disease of cardiac Muscle via misfolded amyloid Protein fibril deposition
  2. Results in progressive thickening of ventricular walls, with secondary Restrictive Cardiomyopathy
  3. Amyloid also deposits in other tissues
    1. Nerve deposition causing Peripheral Neuropathy, Autonomic Dysfunction (and Orthostatic Hypotension), and Erectile Dysfunction
    2. Tendon deposition resulting in Biceps Tendon Rupture and bilateral Carpal Tunnel Syndrome (esp. older patients)
      1. Musculoskeletal symptoms may precede cardiovascular manifestations by 7 years
  4. More than 30 amyloid subtypes exist (9 affect heart), but 2 types predominate (98%) in Cardiac Amyloidosis
    1. Monoclonal Immunoglobulin Light Chains (AL)
      1. Monoclonal Gammopathy (Hematologic Malignancy)
      2. Associated with high mortality in first year without prompt diagnosis and treatment
    2. Transthyretin or TTR transport Protein (ATTR)
      1. Acquired or Wild-Type (ATTRwt)
      2. Hereditary or Variant (ATTRv)
        1. Amyloidogenic V142I variant of the transthyretin (TTR) affects up to 4% of those with West African heritage

IV. Indications: Screening

  1. Left Ventricular Wall Thickness >=12 mm AND
  2. At least 1 red flag or clinical scenario
    1. Heart Failure in age >=65 years
    2. Aortic Stenosis >=65 years
    3. Previously hypertensive, but now normotensive or hypotensive
    4. Autonomic Dysfunction or sensory involvement
    5. Peripheral Polyneuropathy
    6. Proteinuria
    7. Skin Bruising
    8. Bilateral Carpal Tunnel Syndrome
    9. Ruptured biceps tendon
    10. Cardiac MRI with subendocardial or transmural Late Gadolinium Enhancement (LGE) or increased extracellular volume (ECV)
    11. Reduced longitudinal strain with apical sparing
    12. Decreased QRS voltage to mass ratio
    13. Pseudo Q Waves on EKG
    14. AV conduction disease
    15. Possible Family History of Amyloidosis

V. Imaging: Bone Scan

  1. Diphosphate Scintigraphy (Tc99-DPD/PYP/HMDP with SPECT)
  2. Primarily indicated in ATTR type Amyloidosis
  3. Grading of increased cardiac uptake (Grade 2 or 3 should raise suspicion for Cardiac Amyloidosis)
    1. Grade 0: Myocardial uptake ABSENT, and bone uptake normal
    2. Grade 1: Myocardial uptake LOWER than bone uptake
    3. Grade 2: Myocardial uptake SIMILAR to bone uptake
    4. Grade 3: Myocardial uptake GREATER than bone, and reduced bone uptake

VI. Imaging: Echo Criteria for Cardiac Amyloidosis

  1. Unexplained left ventricular (LV) thickness >=12 mm AND
  2. One of the 2 echo criteria sets positive
    1. Echo with >=2 of the following
      1. Grade 2 or worse Diastolic Dysfunction
      2. Reduced tissue doppler s', e' and a' wave velocities (<5 cm/s)
      3. Decreased global longitudinal LV strain (absolute value <-15%)
    2. Mutiparametric echo score >=8 points (total cummulative points)
      1. Score 3: Relative LV Wall Thickness (IVS+PWT)/LVEDD >0.6
      2. Score 1: Doppler E wave/e' wave velocity >11
      3. Score 2: TAPSE <=19 mm
      4. Score 1: LV global longitudinal strain absolute value <= -13%
      5. Score 3: Systolic longitudinal strain apex to base ratio >2.9

VII. Imaging: Cardiac MRI Criteria for Cardiac Amyloidosis

  1. Indicated when type of Cardiomyopathy is unclear
  2. Findings
    1. Diffuse subendocardial or transmural Late Gadolinium Enhancement (LGE, required for diagnosis)
    2. Abnormal gadolinium kinetics with myocardial nulling preceding or coinciding with blood pool (required for diagnosis)
    3. Increased extracellular volume (ECV) >=0.40% (supportive, but not diagnostic, and not required for diagnosis)

VIII. Labs

  1. Serum and Urine immunofixation (SPIE, UPIE)
    1. Most important first test in suspected Cardiac Amyloidosis (to identify AL Type)
    2. Detects monoclonal Protein (clonal Ig or light chains)
    3. Normal in ATTR type of Cardiac Amyloidosis
    4. Positive in AL Type and should prompt urgent hematology referral and biopsy
  2. Serum free light chains
    1. Measures ratio of Serum K+appa to lambda light chains
    2. Detects Detecting low-level clonal light chain production
    3. Normal range varies by assay, but a ratio far from 1:1 may suggest clonal production
    4. Normal in ATTR type of Cardiac Amyloidosis (abnormal ratio in AL type)
  3. Other findings
    1. NT-proBNP elevated out of porportion to degree of Heart Failure
    2. Serum Troponin persistently elevated (despite non-occlusive Coronary Vessels)
    3. Renal Insufficiency and Proteinuria may be present in some types of Amyloidosis (including AL)

IX. Diagnosis

  1. Step 1: Initial, Noninvasive Tests (sufficient alone for ATTR type diagnosis)
    1. Echocardiogram criteria as above (obtain in all suspected cases) AND
    2. Serum Markers (obtain in all suspected cases to exclude AL type)
      1. Positive results suggest AL type (which requires urgent biopsy for diagnosis)
      2. Serum free light chains negative in ATTR
      3. Serum and Urine immunofixation (SPIE, UPIE) negative in ATTR
    3. Other imaging to confirm ATTR diagnosis (sufficient without biopsy)
      1. Diphosphate Scintigraphy (Tc99-DPD/PYP/HMDP with SPECT) with increased cardiac uptake (Grade 2 or 3)
      2. Cardiac MRI (see imaging)
  2. Step 2: Invasive Tests if nondiagnostic initial tests (and biopsy is required for AL type diagnosis)
    1. Cardiac biopsy positive for amyloid OR
    2. Extracardiac biopsy positive for amyloid AND echo and Cardiac MRI consistent with amyloid

X. Management: General and Secondary Associated Conditions

  1. Aortic Stenosis
    1. Associated with worse prognosis
    2. Consider TAVR
  2. Heart Failure
    1. Treat with Diuretics and fluid control
    2. Avoid Beta Blockers and ACE/ARBs
    3. LVAD is not indicated in most patients
    4. Consider Heart Transplant
  3. Atrial Fibrillation
    1. Amiodarone is the preferred Antiarrhythmic in Cardiac Amyloidosis
    2. Exercise caution with Digoxin
    3. Risk of complications with electrical cardioversion
      1. Atrial Fibrillation often recurrs after cardioversion
      2. Obtain TEE echo before cardioversion to exclude cardiac thrombus
  4. Thromboembolism
    1. Increased risk in Amyloidosis
    2. Anticoagulation for Atrial Fibrillation (regardless of CHADS-VASC)
  5. Conduction Disorders
    1. Pacemaker indications are the same as without Amyloidosis
  6. Ventricular Arrhythmia
    1. Transvenous Implantable Cardioverter-Defibrillator
      1. Indicated for secondary prevention of ventricular Arrhythmia (not primary)
  7. Neuropathy
    1. Refer to neurology
    2. Genetic Silencers may be considered

XI. Management: Amyloidosis Specific

  1. Light-chain Amyloidosis (AL)
    1. Urgent referral for biopsy
    2. Treated as a Hematologic Malignancy (Monoclonal Gammopathy)
  2. Transthyretin Amyloidosis (ATTR)
    1. Synthesis suppression
      1. Liver Transplant
      2. Genetic Editing
      3. Genetic Silencers (e.g. Inotersan)
    2. TTR Stabilization
      1. Diflunisal
      2. Tafamidis or Acoramidis
    3. Elimination of amyloid deposits
      1. Doxycycline
      2. Antibodies (PRX004, NI006)
      3. Epigallocatechin gallate (EGCG) in Green Tea

XII. Resources

  1. Cardiac Amyloidosis (Curbsiders)
    1. https://thecurbsiders.com/curbsiders-podcast/427-kittleson-rules-amyloidosis

XIII. References

  1. Garcia-Pavia (2021) Eur Heart J 42(16):1554-68 +PMID: 33825853 [PubMed]

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