ATTR-CM: Transthyretin Amyloid Cardiomyopathy
ATTR-CM stands for Transthyretin Amyloid Cardiomyopathy, a form of cardiac amyloidosis caused by the deposition of transthyretin protein in the heart muscle.
Understanding ATTR-CM
ATTR-CM is a progressive, life-threatening disorder that occurs when transthyretin protein becomes unstable, misfolds, and forms amyloid fibrils that deposit in the heart, causing:
- Restrictive cardiomyopathy
- Heart failure (often with preserved ejection fraction)
- Conduction abnormalities
- Valvular dysfunction
Types of ATTR-CM
ATTR-CM exists in two forms:
ATTRwt (wild-type): Age-related form, previously called "senile" amyloidosis
- More common in older males (typically >60 years)
- Not caused by genetic mutations
ATTRv (variant) or hATTR: Hereditary form
- Caused by pathogenic variants in the TTR gene
- Common variants affecting the heart include Val122Ile, Leu111Met, and Ile68Leu 1
- Can affect multiple organ systems
Clinical Presentation and Diagnostic Clues
ATTR-CM is often misdiagnosed as other conditions due to its heterogeneous presentation. Key diagnostic clues include:
- Heart failure with preserved ejection fraction (HFpEF)
- Left ventricular wall thickening (≥14 mm) 2
- Discordance between wall thickness on echocardiogram and QRS voltage on ECG 2
- Apical sparing pattern on longitudinal strain imaging
- Intolerance to standard heart failure medications (ACE inhibitors, ARBs, beta-blockers)
- Elevated troponin and NT-proBNP disproportionate to heart failure severity
Associated Conditions That Should Raise Suspicion
- Bilateral carpal tunnel syndrome (especially in men) 2
- Lumbar spinal stenosis 2
- Biceps tendon rupture 2
- Autonomic or sensory polyneuropathy 2
- Severe aortic stenosis 2
Diagnostic Approach
The American College of Cardiology/American Heart Association recommends the following diagnostic algorithm 2:
Initial Screening: When ATTR-CM is suspected, perform:
- Serum and urine immunofixation electrophoresis (IFE)
- Serum free light chain (FLC) assay
If negative for monoclonal proteins:
- Perform bone scintigraphy with 99mTc-PYP (in US) or other tracers (99mTc-DPD, 99mTc-HMDP)
- Grade 2-3 cardiac uptake or heart-to-contralateral ratio >1.5 confirms ATTR-CM
If ATTR-CM is confirmed:
- Perform TTR gene sequencing to differentiate ATTRv from ATTRwt
- Genetic testing is essential for family screening and determining treatment options
Treatment Options
Recent advances have transformed ATTR-CM from an untreatable condition to one with specific therapies:
Tafamidis (Vyndaqel/Vyndamax): FDA-approved TTR stabilizer for ATTR-CM
- Reduces all-cause mortality and cardiovascular hospitalizations in patients with NYHA class I-III symptoms 2
- First-line therapy for both ATTRwt and ATTRv cardiac amyloidosis
Other treatments under investigation:
Prognosis and Disease Progression
Without treatment, ATTR-CM has a poor prognosis:
- Progressive decline in functional capacity (6-minute walk test)
- Deteriorating quality of life
- Increasing hospitalizations
- Median survival of approximately 3-5 years from diagnosis
ATTRv patients typically have more severe disease at baseline and more rapid progression compared to ATTRwt patients 4.
Key Points for Clinical Practice
- ATTR-CM is likely underdiagnosed and should be suspected in elderly patients with heart failure and increased wall thickness
- Non-invasive diagnosis is now possible with bone scintigraphy when combined with absence of monoclonal proteins
- Early diagnosis is crucial as disease-modifying treatments are now available
- Genetic testing is essential to distinguish ATTRv from ATTRwt and guide family screening
Understanding ATTR-CM and its presentation is critical for early diagnosis and treatment, which can significantly improve patient outcomes and quality of life.