What is the recommended diagnostic work‑up and first‑line therapy for an older adult with heart failure, unexplained left‑ventricular hypertrophy, low‑voltage electrocardiogram and systemic symptoms suggestive of transthyretin amyloid cardiomyopathy?

Diagnosis and Treatment of ATTR Cardiac Amyloidosis

In an older adult with heart failure, unexplained left ventricular hypertrophy, low-voltage ECG, and systemic symptoms, immediately screen for monoclonal light chains with serum and urine immunofixation electrophoresis plus serum free light chains; if negative, proceed directly to bone scintigraphy with ⁹⁹ᵐTc-PYP (or DPD/HMDP), which confirms ATTR-CM when myocardial uptake is grade ≥2 or heart-to-contralateral ratio >1.5, then perform TTR gene sequencing to distinguish wild-type from hereditary disease, and initiate tafamidis for NYHA class I-III symptoms to reduce cardiovascular morbidity and mortality. 1, 2

Diagnostic Algorithm

Step 1: Recognize Clinical Red Flags

The combination of specific cardiac and extracardiac features should trigger immediate suspicion for ATTR-CM:

Cardiac features:

• Left ventricular wall thickness ≥14 mm with fatigue, dyspnea, or edema 1
• Voltage-to-mass discordance: low QRS voltage (<0.5 mV in limb leads) despite increased wall thickness on echocardiography 1, 3
• Heart failure with preserved ejection fraction (HFpEF), particularly in men 1, 4
• Intolerance to ACE inhibitors or beta-blockers 1
• Atrial arrhythmias or unexplained need for pacemaker 1

Extracardiac red flags:

• Bilateral carpal tunnel syndrome (present in up to 50% of ATTR-CM patients) 1, 4
• Lumbar spinal stenosis 1, 4
• Biceps tendon rupture 1, 5
• Autonomic or sensory polyneuropathy with loss of warm/cold discrimination 1
• Postural hypotension or alternating bowel patterns 1

Step 2: Mandatory Monoclonal Light Chain Screening

Before any other diagnostic test is interpreted, you must exclude AL amyloidosis by screening for monoclonal proteins. 1, 2

Perform all three tests simultaneously:

• Serum immunofixation electrophoresis
• Urine immunofixation electrophoresis
• Serum free light chain assay

This combination achieves >99% sensitivity for detecting AL amyloidosis. 2 Critical trap: Bone scintigraphy can be positive in AL amyloidosis, making it impossible to distinguish ATTR from AL without prior light chain exclusion. 2 Never interpret nuclear imaging in isolation. 2

Step 3: Bone Scintigraphy for Non-Invasive Diagnosis

If monoclonal protein screening is negative, proceed immediately to ⁹⁹ᵐTc-PYP (U.S.), DPD, or HMDP bone scintigraphy. 1, 2

Diagnostic criteria:

• Myocardial uptake graded 2 or 3 (Perugini score) 1, 2
• Heart-to-contralateral chest ratio (H/CL) >1.5 on 1-hour imaging 1, 2

When bone scintigraphy shows grade ≥2 uptake and monoclonal light chains are absent, ATTR-CM is confirmed without need for endomyocardial biopsy. 1, 2 This non-invasive approach has very high specificity and positive predictive value. 2

Step 4: TTR Gene Sequencing

After confirming ATTR-CM, TTR gene sequencing is mandatory to differentiate hereditary (ATTRv) from wild-type (ATTRwt) disease. 1, 2

• Perform genetic testing even without family history, as penetrance varies between families 1, 2
• Absence of pathogenic TTR mutation confirms wild-type ATTR 2
• If variant identified, refer to genetic counselor and screen family members 1

Step 5: When to Consider Endomyocardial Biopsy

Biopsy is NOT required when:

• Echocardiography or cardiac MRI shows typical findings AND
• Monoclonal light chain screening is negative AND
• Bone scintigraphy demonstrates grade ≥2 uptake 2, 3

Biopsy is indicated only when:

• Non-invasive results are equivocal 2
• Monoclonal protein is present (to distinguish AL from ATTR) 1

Critical trap: Biopsies from sites not clinically involved have high false-negative rates, especially in ATTR. 2 After confirming amyloid on Congo red staining, use mass spectrometry (not immunohistochemistry alone) to type the amyloid protein. 2, 3

Supportive Diagnostic Imaging

Echocardiography (First-Line Imaging)

Perform transthoracic echocardiography in all suspected cases. 1, 5, 3

Key findings:

• Biventricular hypertrophy with small cavity size 1, 3
• Biatrial enlargement disproportionate to ventricular dysfunction 5
• Thickened cardiac valves without significant stenosis 1, 5
• Increased interatrial septal thickness 5, 3
• Restrictive transmitral Doppler filling pattern 5, 3
• Apical sparing on longitudinal strain imaging with apical-to-basal strain ratio >2.1 (highly suggestive) 1, 5, 3
• Pericardial effusion 1, 5

Important limitation: Echocardiography cannot distinguish AL from ATTR amyloidosis; further testing is required. 5

Cardiac MRI (When Echo is Suggestive but Equivocal)

Reserve cardiac MRI for cases where echocardiography is suggestive but not definitive. 5, 3

Diagnostic features:

• Diffuse subendocardial or transmural late gadolinium enhancement (LGE) 1, 5, 3
• Elevated native T1 values (>1020-1044 ms) 5, 3
• Elevated extracellular volume (ECV) >0.40 5, 3
• Abnormal gadolinium kinetics with difficulty nulling myocardium 5

Cardiac MRI has 80-92% sensitivity and 87-94% specificity for cardiac amyloidosis. 5 Diffuse subendocardial LGE has 88% sensitivity and 100% specificity specifically for AL amyloidosis. 5

First-Line Treatment

Tafamidis: Disease-Modifying Therapy

In patients with wild-type or hereditary ATTR-CM and NYHA class I-III heart failure symptoms, tafamidis (transthyretin tetramer stabilizer) is indicated to reduce cardiovascular morbidity and mortality. 1

This is a Class 1, Level B-R recommendation from the 2022 AHA/ACC/HFSA guidelines. 1 Tafamidis is currently the sole FDA-approved disease-modifying therapy for ATTR cardiomyopathy. 6, 7

Anticoagulation for Atrial Fibrillation

In patients with cardiac amyloidosis and atrial fibrillation, anticoagulation is reasonable to reduce stroke risk regardless of CHA₂DS₂-VASc score. 1

This is a Class 2a, Level C-LD recommendation. 1 Cardiac amyloidosis carries inherently high thromboembolic risk due to atrial dysfunction and stasis. 1

Heart Failure Management

Critical caveat: Avoid digoxin and calcium channel blockers in ATTR-CM, as these drugs bind to amyloid fibrils causing toxicity and exaggerated hypotensive responses even at therapeutic levels. 3

Individualize diuretic therapy for volume management, but recognize that patients often require higher filling pressures due to restrictive physiology. 6, 7

Common Diagnostic Pitfalls

• Never rely solely on bone scintigraphy without prior monoclonal protein screening 2, 3
• Do not assume all monoclonal proteins indicate AL amyloidosis—tissue confirmation is required 3
• Do not dismiss ATTR-CM based on absence of family history—wild-type ATTR accounts for the majority of cases and occurs in older adults without genetic predisposition 1, 4
• Recognize that up to 10-15% of older adults with HFpEF may have unrecognized wild-type ATTR 4
• ATTR-CM is frequently underdiagnosed because knowledge is fragmented among specialties and symptom presentation is heterogeneous 2