In elderly patients, especially men over 70, with severe aortic stenosis, what is the association with cardiac amyloidosis (wild‑type transthyretin and light‑chain)?

Association Between Aortic Valve Disease and Cardiac Amyloidosis

In elderly patients with severe aortic stenosis, particularly men over 70, transthyretin cardiac amyloidosis (predominantly wild-type ATTR) coexists in approximately 6-25% of cases, representing a clinically significant and underdiagnosed dual pathology that substantially worsens prognosis. 1, 2, 3

Prevalence and Epidemiology

The association between aortic stenosis (AS) and cardiac amyloidosis (CA) is far more common than historically recognized:

• Approximately 16% of patients with severe AS undergoing aortic valve replacement have transthyretin cardiac amyloidosis, with prevalence ranging from 4-16% in patients over 65 years, and up to 25% in certain elderly cohorts 2, 3, 4
• Wild-type ATTR (ATTRwt) is the predominant form found in AS patients, as this represents age-related misfolding of normal transthyretin protein 5, 4
• Light-chain (AL) amyloidosis coexistence with AS is less common but carries worse prognosis 6, 5

Pathophysiological Connection

The relationship between AS and cardiac amyloidosis involves shared mechanisms:

• Both conditions are markers of aging, with misfolded amyloid proteins infiltrating not only the myocardium but also the aortic valve tissue itself, leading to tissue damage that causes or worsens valve stenosis 3, 7
• Amyloid deposition in the myocardial interstitium disrupts myocyte function, increasing myocardial stiffness and impairing relaxation, resulting in restrictive cardiomyopathy with diastolic dysfunction 5, 8
• The combined insult of pressure overload from AS and infiltrative disease from amyloidosis creates a unique phenotype where NT-proBNP levels, diastolic dysfunction, and troponin elevation resemble isolated ATTR more than isolated AS 9

Clinical Recognition: Red Flags for Screening

The 2022 AHA/ACC/HFSA guidelines recommend screening for cardiac amyloidosis when LV wall thickness ≥14 mm is present with specific clinical contexts 1:

Electrocardiographic Clues

• Low QRS voltage in limb leads despite ventricular wall thickening on echocardiography (present in ~50% of CA patients) - this voltage-mass discordance is pathognomonic 1, 6, 8
• Pseudoinfarct pattern in precordial leads 6, 8
• Conduction abnormalities including atrioventricular block 6
• Atrial fibrillation from atrial amyloid deposition 6

Associated Clinical Conditions

The guidelines specifically highlight these "red flag" associations with AS that should trigger amyloidosis evaluation 1:

• Bilateral carpal tunnel syndrome (particularly important in elderly men) 1, 6
• Lumbar spinal stenosis 1
• Autonomic or sensory polyneuropathy 1, 6
• Heart failure with preserved ejection fraction (HFpEF) 1, 6

Echocardiographic Features

• Apical sparing pattern of LV longitudinal strain impairment 1
• Increased LV wall thickness with small chamber size 5, 8
• Restrictive filling pattern with elevated filling pressures 6, 8

Diagnostic Algorithm

When AS and CA are suspected to coexist, the 2022 AHA/ACC/HFSA guidelines provide a Class 1 recommendation for the following sequential approach 1:

Step 1: Screen for Monoclonal Light Chains (Class 1, LOE B-NR)

• Obtain serum and urine immunofixation electrophoresis AND serum free light chains to exclude AL amyloidosis 1
• This must be done first because bone scintigraphy can be positive in both AL and ATTR 1

Step 2: Bone Scintigraphy if Light Chains Negative (Class 1, LOE B-NR)

• Perform technetium-99m pyrophosphate (99mTc-PYP) bone scintigraphy to confirm ATTR cardiac amyloidosis 1, 3
• Perugini grade 2 or 3 uptake with negative light chain screen is diagnostic of ATTR without need for biopsy 1, 9

Step 3: Genetic Testing (Class 1, LOE B-NR)

• Once ATTR is confirmed, perform TTR gene sequencing to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt) 1
• This distinction affects family screening and has prognostic implications 1

Supportive Testing

• Elevated BNP/NT-proBNP (93% sensitivity, 90% specificity for cardiac involvement) 8
• Cardiac MRI showing diffuse subendocardial late gadolinium enhancement 1, 8
• Elevated high-sensitivity troponin 9

Prognostic Implications

The coexistence of AS and CA significantly worsens outcomes compared to either condition alone:

• Patients with AS-ATTR have higher all-cause mortality after aortic valve replacement compared to AS alone 1, 2
• Maximum LV wall thickness is a major prognostic determinant in dual pathology, regardless of age, LVEF, or type of valve intervention 1
• The AS-ATTR phenotype reflects early-stage amyloid infiltration, but the combined insult resembles isolated ATTR in terms of myocardial stress and damage 9
• Median survival in AL amyloidosis with cardiac involvement is only 13 months (4 months with heart failure), compared to 75 months for ATTRwt 6, 5

Management Considerations

Even after successful treatment of AS with transcatheter aortic valve replacement (TAVR), ATTR-specific therapy is likely beneficial 9:

• Mortality is reduced in patients with AS-CA after TAVR, but outcomes remain worse than AS alone 2, 3
• The presence of CA should not preclude valve intervention, as symptomatic AS requires treatment 4
• ATTR-specific therapies (tafamidis, patisiran, inotersen) have changed the natural history and should be considered after valve replacement 7

Critical Clinical Pitfall

The major diagnostic pitfall is attributing all cardiac symptoms and imaging findings to AS alone without considering coexistent amyloidosis 7. The shared clinical features (dyspnea, fatigue, LV hypertrophy) make this association "misleading" and easily missed 7. Systematic screening based on the red flags above is essential, as early diagnosis of ATTR enables disease-modifying therapy that was previously unavailable 7.