Cardiac Amyloidosis

A 72 year old male presents to the cardiology clinic with progressive exertional dyspnea, fatigue, and bilateral lower limb edema over several months. He reports a prior history of bilateral carpal tunnel syndrome and lumbar spinal stenosis several years before the onset of cardiac symptoms. Vital signs show blood pressure of 110/70 mm Hg and pulse rate of 78 beats per minute. On examination, there is elevated jugular venous pressure and bilateral pitting edema. Lungs are clear. Electrocardiography shows low or discordant QRS voltage relative to increased wall thickness. Echocardiography reveals concentric left ventricular wall thickening, small left ventricular cavity, biatrial enlargement, restrictive filling pattern, and an apical sparing pattern on global longitudinal strain. Serum and urine testing show no monoclonal protein. Bone scintigraphy with Tc-99m PYP demonstrates Perugini grade 3 myocardial uptake. Diagnosis?

Diagnosis is transthyretin cardiac amyloidosis, most likely wild type ATTR cardiomyopathy.

1. Definition

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded amyloid fibrils in the myocardium, leading to restrictive physiology, heart failure, arrhythmias, and conduction abnormalities.

2. Major Types

1. AL amyloidosis
• Due to immunoglobulin light chains from a plasma cell dyscrasia
• Rapidly progressive with frequent multiorgan involvement
2. ATTR amyloidosis
• Due to misfolded transthyretin protein
• Includes:
1. Wild type ATTR, typically affecting older men
2. Variant ATTR, due to TTR gene mutation, often with neuropathy

3. Why It Is Underdiagnosed

1. Mimics heart failure with preserved ejection fraction
2. Often attributed to hypertensive heart disease or aging myocardium
3. Extracardiac clues may precede cardiac symptoms by 5 to 7 years, especially in ATTR

4. Clinical Red Flags

4.1 Cardiac

1. HFpEF or borderline EF with increased wall thickness
2. Biatrial enlargement and restrictive filling pattern
3. Low or discordant ECG voltage relative to wall thickness
4. Elevated troponin or NT-proBNP out of proportion to symptoms
5. Atrial fibrillation or conduction disease

4.2 Extracardiac

1. Bilateral carpal tunnel syndrome
2. Lumbar spinal stenosis
3. Biceps tendon rupture
4. Peripheral neuropathy
5. Autonomic dysfunction, including orthostatic hypotension or GI dysmotility
6. Proteinuria or nephrotic syndrome, more suggestive of AL amyloidosis
7. Macroglossia, also suggestive of AL amyloidosis

5. Pathophysiology

1. Protein misfolding leads to formation of beta sheet amyloid fibrils
2. Deposition occurs in the extracellular myocardial space
3. Results in:
1. Concentric wall thickening without true hypertrophy
2. Diastolic dysfunction and restrictive physiology
3. Conduction system infiltration
4. Fixed stroke volume, leading to poor tolerance of vasodilators and beta blockers

Extracardiac involvement may affect nerves, tendons, ligaments, gastrointestinal tract, and kidneys

6. Diagnostic Approach

6.1 Step 1: Exclude AL Amyloidosis

This is essential because AL amyloidosis is a medical emergency

1. Serum immunofixation electrophoresis
2. Urine immunofixation electrophoresis
3. Serum free light chain assay

6.2 Echocardiography

1. Concentric LV wall thickening
2. Small LV cavity
3. Biatrial enlargement
4. Restrictive filling pattern
5. Apical sparing on strain imaging

6.3 ECG

1. Low or discordant voltage relative to LV thickness
2. Conduction abnormalities such as AV block or atrial fibrillation

6.4 Cardiac MRI

1. Diffuse subendocardial or transmural late gadolinium enhancement
2. Difficulty nulling the myocardium
3. T1 mapping and extracellular volume quantification for disease assessment

6.5 Nuclear Imaging

1. Tc-99m PYP, DPD, or HMDP scanning
2. Perugini grade 2 or 3 uptake with negative monoclonal protein confirms ATTR noninvasively

6.6 Genetic Testing

Performed after ATTR diagnosis to distinguish:

1. Wild type ATTR
2. Variant ATTR

6.7 Biopsy

Indicated when:

1. AL amyloidosis is suspected
2. Imaging findings are equivocal
3. Presentation is atypical

Endomyocardial biopsy is most sensitive. Congo red staining shows apple green birefringence, and mass spectrometry confirms subtype.

7. Management

7.1 AL Amyloidosis

1. Urgent hematology referral
2. Plasma cell directed chemotherapy
3. Autologous stem cell transplantation in selected patients
4. Supportive cardiac care

7.2 ATTR Amyloidosis

1. Tafamidis
• First line therapy for ATTR cardiomyopathy
• Stabilizes transthyretin
• Improves survival and reduces hospitalizations
2. Gene silencing therapies
• Patisiran and inotersen, mainly for variant ATTR with neuropathy
• Vutrisiran, given subcutaneously every 12 weeks, with emerging evidence for cardiovascular benefit
3. Supportive therapy
• Loop diuretics, carefully titrated

8. Important Management Principles

1. Avoid or use extreme caution with digoxin
2. Avoid non-dihydropyridine calcium channel blockers
3. Beta blockers are often poorly tolerated
4. Avoid aggressive vasodilators if poorly tolerated
5. Anticoagulate all patients with atrial fibrillation
6. Pacemaker may be required for conduction disease
7. CRT if standard indications are met
8. ICD is not routinely indicated unless clear arrhythmic risk is present

9. Monitoring and Follow Up

1. Serial NT-proBNP and troponin levels
2. Echocardiography with strain imaging
3. Cardiac MRI or nuclear imaging for disease progression
4. Functional assessment with 6 minute walk test and quality of life measures

10. Key Clinical Insight

Heart failure with preserved ejection fraction, increased wall thickness without hypertension, low or discordant ECG voltage, apical sparing on strain imaging, and extracardiac features such as bilateral carpal tunnel syndrome strongly suggest cardiac amyloidosis, particularly ATTR.

11. Exam Level Pearls

1. Low voltage ECG with thick myocardium is a classic clue
2. Always exclude AL amyloidosis first
3. Perugini grade 2 to 3 uptake confirms ATTR if monoclonal proteins are absent
4. Apical sparing pattern is highly suggestive
5. Extracardiac features may precede cardiac symptoms by years
6. Tafamidis is first line therapy for ATTR cardiomyopathy
7. AL amyloidosis is a medical emergency requiring urgent treatment