# Cardiac Amyloidosis

## Overview and Classification

### Comparison of Major Cardiac Amyloidosis Subtypes

| Feature | Wild-Type ATTR | Hereditary ATTR | AL (Light Chain) |
|---|---|---|---|
| Precursor protein | Normal transthyretin | Mutant transthyretin | Monoclonal light chains (lambda > kappa) |
| Age at presentation | >65 years (predominantly male) | Variable (mutation-dependent) | 50-70 years |
| Inheritance | None (age-related) | Autosomal dominant | None (acquired plasma cell neoplasm) |
| Key mutations | -- | V122I (cardiac, 3-4% African Americans), T60A, V30M (neuropathic) | -- |
| Cardiac involvement | Primary organ | Variable by mutation | 50-75% |
| Extracardiac features | Carpal tunnel, spinal stenosis, biceps tendon rupture | Peripheral/autonomic neuropathy + cardiac | Nephrotic syndrome, macroglossia, periorbital purpura |
| PYP/DPD scan | Grade 2-3 uptake | Grade 2-3 uptake | Usually negative (but some uptake possible) |
| Median survival (untreated cardiac) | 3.5-5 years | Variable | 6-12 months |
| Disease-modifying therapy | Tafamidis, gene silencers | Tafamidis, gene silencers, combined heart-liver transplant | CyBorD + daratumumab (ANDROMEDA); ASCT if eligible |

### Types of Cardiac Amyloidosis

Cardiac amyloidosis encompasses several distinct disease entities defined by the precursor protein that misfolds and deposits as amyloid fibrils within the myocardium. Transthyretin amyloidosis represents the most common cause of cardiac amyloidosis and exists in two forms. Wild-type transthyretin amyloidosis, previously termed senile systemic amyloidosis, is an age-related condition predominantly affecting males over 65 years of age with cardiac-dominant disease. Autopsy studies suggest its prevalence may reach 10 to 16% of the heart failure with preserved ejection fraction population aged over 60, indicating massive underdiagnosis. Hereditary transthyretin amyloidosis follows autosomal dominant inheritance patterns, with over 130 known transthyretin mutations identified. The V122I mutation, carried by 3 to 4% of African Americans, produces a cardiac phenotype. The T60A mutation causes both cardiac and neurologic manifestations, while the V30M mutation is predominantly neuropathic with younger onset.

Light chain amyloidosis results from a monoclonal plasma cell neoplasm, with lambda light chains more commonly deposited than kappa chains. Cardiac involvement occurs in 50 to 75% of cases, and the disease is characteristically multisystem, affecting the kidneys, liver, nerves, and soft tissues. Untreated, light chain amyloidosis with cardiac involvement carries the worst prognosis of any amyloid subtype, with a median survival of only 6 to 12 months. Secondary amyloidosis, caused by the amyloid A protein deposited in chronic inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, and chronic infections, rarely involves the heart, primarily affecting the kidneys and liver. Other rare subtypes including ALECT2, AFib, and apolipoprotein AI very rarely cause cardiac disease.

### Epidemiology -- An Underdiagnosed Epidemic

The recognition of wild-type transthyretin amyloidosis has expanded dramatically with improved diagnostic capabilities. It has been identified in 13% of heart failure with preserved ejection fraction hospitalizations in one study, 6% of patients undergoing transcatheter aortic valve replacement, and 5% of carpal tunnel surgery biopsies. Historical prevalence figures were dramatically underestimated, and improved diagnostics including technetium-99m pyrophosphate scintigraphy and accessible genetic testing are revealing the true disease burden. The mean time from symptom onset to diagnosis remains 2 to 3 years, a critical delay because earlier diagnosis enables earlier initiation of tafamidis, which provides the greatest benefit in NYHA Class I-II patients.

## Clinical Manifestations

### Cardiac

The cardiac manifestations of amyloidosis reflect progressive infiltration of the myocardium with amyloid deposits. Biventricular wall thickening of 12 mm or greater, often reaching 15 to 20 mm, occurs without corresponding left ventricular hypertrophy on the electrocardiogram, creating the pathognomonic voltage-mass mismatch. Heart failure develops with preserved or mildly reduced ejection fraction, accompanied by diastolic dysfunction of Grade II to III severity and elevated filling pressures. Biatrial enlargement and small pericardial effusion, present in approximately 50% of cases, are common accompanying findings. Advanced disease produces a restrictive filling pattern with a deceleration time below 150 milliseconds.

Atrial fibrillation occurs in 40 to 70% of patients and is poorly tolerated hemodynamically. Importantly, left atrial appendage thrombus risk is elevated even in patients maintaining sinus rhythm due to atrial infiltration and stasis. Conduction disease is frequent, manifesting as first-degree atrioventricular block, bundle branch block with right bundle branch block more common in transthyretin amyloidosis, and progression to high-degree atrioventricular block requiring permanent pacing.

### Extracardiac Red Flags

Several extracardiac findings serve as important diagnostic clues that should prompt cardiac evaluation. Bilateral carpal tunnel syndrome precedes the cardiac diagnosis by a median of 5 to 10 years in transthyretin amyloidosis and should trigger cardiac workup in men over 60. Lumbar spinal stenosis is associated with wild-type transthyretin deposition in the ligamentum flavum. Biceps tendon rupture, producing the "Popeye sign," is specific to transthyretin amyloidosis. Peripheral neuropathy follows a length-dependent sensorimotor pattern, with autonomic dysfunction manifesting as orthostatic hypotension, gastroparesis, and erectile dysfunction. These neurologic features are more prominent in hereditary transthyretin amyloidosis, particularly the V30M mutation, and in light chain amyloidosis.

Several findings are specific to light chain amyloidosis and their presence helps distinguish it from transthyretin disease. Periorbital purpura, known as "raccoon eyes," is pathognomonic for light chain amyloidosis and does not occur in transthyretin disease. Macroglossia, affecting approximately 15% of light chain amyloidosis patients and producing scalloped tongue edges from teeth impressions, is another light chain-specific finding. Nephrotic syndrome occurs predominantly in light chain disease, while transthyretin amyloidosis may cause only mild renal insufficiency. Hepatomegaly with elevated alkaline phosphatase out of proportion to transaminases is associated with light chain disease.

## Diagnostic Approach

### Echocardiography

Echocardiographic evaluation reveals increased biventricular wall thickness, with the interventricular septum often measuring 14 to 18 mm. The historically described "granular sparkling" appearance has become less reliable with modern harmonic imaging techniques. Diastolic dysfunction is typically Grade II to III, with an elevated E/e-prime ratio. The left ventricular cavity is small with reduced stroke volume, and a low indexed stroke volume below 35 mL/m squared is common.

The global longitudinal strain pattern with apical sparing has emerged as one of the most diagnostically useful echocardiographic findings. Basal and mid-wall segments demonstrate severely impaired longitudinal strain while the apex is relatively preserved, creating the characteristic "cherry on top" or "Christmas tree" pattern on the bullseye strain plot. A relative apical longitudinal strain exceeding 1.0 has approximately 90% sensitivity for cardiac amyloidosis and should prompt immediate further workup. Additional findings include a thickened interatrial septum exceeding 6 mm, thickened atrioventricular valve leaflets, and right ventricular free wall thickening. Tricuspid annular plane systolic excursion may be preserved early through right ventricular compensation but declines with disease progression.

### Electrocardiogram

The electrocardiogram frequently demonstrates low voltage, defined as limb lead QRS amplitude below 5 mm and precordial lead amplitude below 10 mm, present in 50 to 60% of light chain amyloidosis and approximately 30% of transthyretin amyloidosis. The combination of low voltage with increased wall thickness on echocardiography, the voltage-mass mismatch, is highly suggestive of cardiac amyloidosis. A pseudo-infarct pattern with pathologic Q waves in the anterior or inferior leads without underlying coronary disease occurs in 40 to 70% of patients. Conduction abnormalities including PR prolongation, right bundle branch block especially in transthyretin disease, left bundle branch block, and high-degree atrioventricular block are common. Atrial fibrillation is present in 40 to 70% of cases. Poor R-wave progression may mimic anterior myocardial infarction.

### Cardiac MRI

Cardiac magnetic resonance imaging demonstrates several characteristic findings. Diffuse subendocardial or transmural late gadolinium enhancement is typical, and difficulty nulling the myocardium on the TI scout sequence, where blood and myocardium null at the same time, is pathognomonic. Native T1 mapping shows elevated values exceeding 1100 milliseconds at 1.5 Tesla, while the extracellular volume fraction is markedly elevated, typically exceeding 0.40 and often reaching 0.50 to 0.60 in advanced disease. T1 and extracellular volume fraction correlate with amyloid burden and are increasingly used for monitoring treatment response. Cardiac MRI provides more accurate wall thickness measurement and tissue characterization than echocardiography. In patients with severe renal failure, which affects many light chain amyloidosis patients, non-contrast techniques including native T1 mapping without gadolinium remain diagnostically valuable.

### Nuclear Imaging -- Tc-99m PYP/DPD/HMDP

Technetium-99m bone scintigraphy represents a transformative diagnostic advance for cardiac amyloidosis. In the United States, technetium-99m pyrophosphate is used, while technetium-99m DPD or HMDP is used in Europe. The mechanism involves binding of the radiotracer to calcium-containing amyloid fibrils, with preferential labeling of transthyretin deposits. Imaging is graded from Grade 0, indicating no cardiac uptake, through Grade 3, indicating uptake greater than bone. A heart-to-contralateral ratio of 1.5 or greater at 1 hour is considered positive.

The landmark contribution of this technique lies in the Gillmore criteria, which allow diagnosis of transthyretin cardiac amyloidosis without biopsy when Grade 2 or 3 uptake or a heart-to-contralateral ratio of 1.5 or greater is present in conjunction with complete absence of a monoclonal protein on serum protein electrophoresis, urine protein electrophoresis, and serum free light chain assay. This combination achieves a sensitivity of 99% and specificity of 86% for transthyretin amyloidosis. A critical caveat is that some light chain amyloidosis cases show pyrophosphate uptake, making exclusion of a monoclonal protein absolutely mandatory before accepting a non-invasive diagnosis of transthyretin disease. If any monoclonal protein is detected, tissue biopsy is required to differentiate light chain from transthyretin amyloidosis, as both may coexist.

### Tissue Diagnosis

Tissue biopsy options include abdominal fat pad aspiration, which uses Congo red staining and achieves a sensitivity of approximately 70 to 80% for light chain amyloidosis and 45 to 70% for transthyretin amyloidosis with low procedural morbidity. Endomyocardial biopsy represents the gold standard, demonstrating Congo red staining with characteristic apple-green birefringence under polarized light. Typing is performed by immunohistochemistry when findings are clear-cut or by mass spectrometry for ambiguous cases. Bone marrow biopsy is essential for light chain amyloidosis staging and characterization of the plasma cell clone. Other potential biopsy sites include the labial salivary gland, rectum, skin, and carpal tunnel tissue if the patient is undergoing surgery for that indication.

### Typing -- Critical Step

Definitive typing of the amyloid deposit is the most critical step in the diagnostic algorithm, as the treatment approach differs fundamentally between light chain and transthyretin amyloidosis. Mass spectrometry of amyloid deposits identifies the precursor protein definitively and is the most accurate typing method. Immunohistochemistry is less reliable, particularly for transthyretin amyloidosis where antibodies may be less specific. Genetic testing with transthyretin gene sequencing must be performed for all patients with transthyretin amyloidosis to distinguish wild-type from hereditary disease, as this distinction has implications for family screening and treatment selection.

<image>
A comprehensive diagnostic pathway for cardiac amyloidosis displayed as a flowchart. Start with "Clinical Suspicion: unexplained LVH (especially with low voltage ECG), HFpEF in elderly male, bilateral carpal tunnel, peripheral neuropathy, autonomic dysfunction." Step 1: "Echocardiography with GLS strain analysis" with an inset showing the apical sparing bullseye pattern (red at base/mid, blue at apex, labeled RALS > 1.0) and thickened walls (16mm IVS). Step 2: "Simultaneous workup in parallel" with two branches. Branch A (left): "Exclude AL amyloidosis: serum free light chains (kappa/lambda ratio), SPEP with immunofixation, UPEP with immunofixation. If ANY abnormality → hematology referral + tissue biopsy (fat pad, EMB, or bone marrow)." Branch B (right): "Tc-99m PYP bone scintigraphy: acquire planar + SPECT images at 1 hour and 3 hours." PYP results matrix: Grade 0 or H/CL <1.5 + normal sFLC → "Cardiac amyloid unlikely; consider CMR, EMB if suspicion persists." Grade 2-3 or H/CL >=1.5 + NORMAL sFLC/SPEP/UPEP → "ATTR-CM confirmed (no biopsy needed); proceed to TTR genetic testing → wild-type vs hereditary." Grade 2-3 + ABNORMAL sFLC → "Cannot distinguish AL from ATTR; tissue biopsy with mass spectrometry REQUIRED." Include representative PYP scan images showing Grade 0 (no cardiac uptake) and Grade 3 (intense cardiac uptake greater than bone). Use blue pathway for ATTR, red for AL.
</image>

## Treatment

### AL Amyloidosis -- Hematology-Directed

The treatment of light chain amyloidosis targets the underlying monoclonal plasma cell neoplasm to halt light chain production. The standard first-line regimen has been cyclophosphamide, bortezomib, and dexamethasone (CyBorD). The ANDROMEDA trial established daratumumab plus CyBorD as the new standard of care, demonstrating significantly higher rates of hematologic complete response at 53% compared to 18% with CyBorD alone, along with superior cardiac response rates. Autologous stem cell transplantation remains an option for eligible patients meeting specific criteria: age below 70, NT-proBNP below 5000 pg/mL, troponin T below 0.06, absence of severe autonomic neuropathy, estimated glomerular filtration rate above 50, and adequate cardiac reserve. Conditioning with melphalan achieves the deepest hematologic responses.

Response assessment evaluates both hematologic and organ-specific endpoints. Hematologic response tiers include partial response with a 50% or greater decrease in serum free light chains, very good partial response with a difference in involved and uninvolved free light chains below 40 mg/L, and complete response defined by negative immunofixation with a normal free light chain ratio. Cardiac organ response is defined as a decrease in NT-proBNP of 30% or more and greater than 300 pg/mL. The Mayo 2012 staging system, based on troponin T of 0.025 or greater, NT-proBNP of 1800 or greater, and the difference in involved and uninvolved free light chains of 180 mg/dL or greater, stratifies prognosis from Stage I with a median survival exceeding 8 years to Stage IV with all markers elevated and a median survival of only 6 months.

Supportive cardiac care in light chain amyloidosis requires diuretics, often high-dose loop combined with thiazide diuretics. Several commonly used cardiac medications must be avoided. Beta-blockers are generally poorly tolerated because patients depend on heart rate to maintain cardiac output. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers frequently worsen orthostatic hypotension from autonomic neuropathy. Digoxin is absolutely contraindicated because amyloid fibrils bind digoxin, causing toxicity at therapeutic serum levels.

### ATTR Amyloidosis -- Disease-Modifying Therapies

#### TTR Stabilizers

Tafamidis meglumine at 80 mg daily or tafamidis free acid at 61 mg daily stabilizes the transthyretin tetramer, preventing its dissociation into misfolding monomers. The ATTR-ACT trial demonstrated a 30% reduction in all-cause mortality and a 32% reduction in cardiovascular hospitalization over 30 months, with benefit most pronounced in patients with NYHA Class I-II symptoms. This finding underscores the critical importance of early diagnosis and treatment initiation. Acoramidis represents a next-generation transthyretin stabilizer that achieves superior stabilization of the transthyretin tetramer, with positive results in the ATTRibute-CM trial for its composite endpoint. Diflunisal, a nonsteroidal anti-inflammatory drug with transthyretin-stabilizing properties, can be used at 250 mg twice daily with limited evidence from a small randomized trial showing reduced progression of neuropathy, though renal and gastrointestinal side effects limit its use in cardiac patients.

#### TTR Gene Silencers

Patisiran is a small interfering RNA that silences hepatic transthyretin messenger RNA, administered as an intravenous infusion every 3 weeks. The APOLLO trial demonstrated dramatic neurologic improvement, and the APOLLO-B trial in cardiomyopathy patients showed improvements in 6-minute walk distance, NT-proBNP, global longitudinal strain, and functional capacity. Vutrisiran is a subcutaneous small interfering RNA administered every 3 months, with positive results in the HELIOS-A neuropathy trial and HELIOS-B cardiomyopathy trial, offering more convenient administration. Inotersen, an antisense oligonucleotide administered subcutaneously weekly, demonstrated efficacy in the NEURO-TTR neuropathy trial but carries risks of thrombocytopenia and glomerulonephritis requiring monitoring, limiting its cardiac use. Eplontersen, a ligand-conjugated antisense oligonucleotide given subcutaneously monthly, offers an improved safety profile over inotersen, with positive results in the NEURO-TTRansform trial.

#### Emerging Therapies

Anti-amyloid antibodies represent a paradigm shift toward active amyloid removal rather than prevention of new deposition. NI006 (coramitug) is a monoclonal antibody targeting deposited transthyretin amyloid with early clinical trial evidence showing regression of amyloid deposits on imaging. CRISPR-based transthyretin gene editing using NTLA-2001 delivers CRISPR-Cas9 via lipid nanoparticles as a single intravenous infusion to knock out the transthyretin gene in hepatocytes, achieving more than 90% sustained transthyretin protein reduction in early trials with the potential to be curative.

### Transplantation

Heart transplantation is considered for selected patients with light chain amyloidosis who have achieved or can achieve hematologic complete response, or for patients with transthyretin amyloidosis with isolated cardiac involvement. Combined heart-liver transplantation for hereditary transthyretin amyloidosis removes the hepatic source of mutant transthyretin protein, thereby eliminating the precursor of amyloid deposition. Liver transplantation alone using the domino concept, where a transthyretin amyloidosis liver is donated to a non-amyloid recipient, is now rarely performed due to the recognized risk of transmitted transthyretin disease in the recipient.

<image>
A treatment algorithm for cardiac amyloidosis divided by type. Two main pathways. Left pathway (red, labeled "AL Amyloidosis"): "Hematology referral → Staging (Mayo 2012) → First-line: Daratumumab + CyBorD (ANDROMEDA) → Response assessment at 3-6 months (hematologic: sFLC, SPEP; cardiac: NT-proBNP, troponin) → If eligible: ASCT → If complete response: surveillance → If refractory: second-line regimens (lenalidomide, pomalidomide, venetoclax) → Heart transplant if end-stage with hematologic CR. Supportive: loop diuretics (high dose), compression stockings, midodrine for orthostatic hypotension. AVOID: beta-blockers, ACEi/ARBs (if orthostatic), digoxin." Right pathway (blue, labeled "ATTR Amyloidosis"): "TTR genetic testing → Wild-type OR Hereditary." For both: "Disease-modifying therapy: TTR stabilizer (tafamidis 61/80mg daily - start EARLY, NYHA I-II for greatest benefit) OR TTR silencer (patisiran IV q3wk, vutrisiran SC q3mo). NYHA I-II: tafamidis/acoramidis (Class I). NYHA III: tafamidis (less evidence, still recommended); consider silencer. Advanced/NYHA IV: transplant evaluation. Hereditary-specific: consider combined heart-liver transplant." Bottom panel: "All patients: diuretic management, AF management (anticoagulation recommended regardless of CHA2DS2-VASc), pacemaker for symptomatic conduction disease, cardiac rehabilitation."
</image>

## Special Considerations

### AF and Thromboembolic Risk

Atrial fibrillation in cardiac amyloidosis carries a high prevalence of 40 to 70% and is associated with elevated intracardiac thrombus risk even among patients maintaining sinus rhythm, owing to atrial stasis from amyloid infiltration and reduced left atrial appendage function. Anticoagulation is recommended for all cardiac amyloidosis patients with atrial fibrillation, both light chain and transthyretin subtypes, regardless of CHA2DS2-VASc score. Either direct oral anticoagulants or warfarin are acceptable. Some experts advocate anticoagulation even for patients in sinus rhythm who demonstrate severely reduced left atrial appendage function.

### Device Therapy

Pacemaker implantation is indicated for symptomatic bradycardia and high-degree atrioventricular block, which is particularly common in transthyretin amyloidosis. Cardiac resynchronization therapy should be considered for pacing-dependent patients with reduced ejection fraction. Implantable cardioverter-defibrillator therapy remains controversial in cardiac amyloidosis because sudden cardiac death in this population often results from pulseless electrical activity or asystole rather than ventricular tachycardia or ventricular fibrillation. Evidence for implantable defibrillator benefit is limited, and decisions should be made on a case-by-case basis, considering factors such as documented ventricular tachycardia episodes and younger age in hereditary disease.

### Cardiac Medications to AVOID in Amyloidosis

| Medication | Reason to Avoid | Severity |
|---|---|---|
| Digoxin | Amyloid fibrils bind digoxin causing toxicity at therapeutic levels | **Absolutely contraindicated** |
| Beta-blockers | Chronotropic dependence; hypotension and reduced CO | Generally poorly tolerated |
| ACE inhibitors/ARBs | Worsens orthostatic hypotension from autonomic neuropathy | Frequently not tolerated |
| Verapamil/diltiazem | Negative inotropic effects; may bind amyloid deposits | Avoid |
| ARNI (sacubitril/valsartan) | May worsen hypotension; limited data | Use with caution |

### Medication Intolerances

Managing the cardiac pharmacology of amyloidosis patients requires awareness of several critical intolerances. Beta-blockers are often poorly tolerated due to chronotropic dependence and may cause hypotension and reduced cardiac output. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers worsen orthostatic hypotension from autonomic neuropathy and are frequently not tolerated. Digoxin is absolutely contraindicated because amyloid fibrils avidly bind the drug, producing toxicity at therapeutic serum levels. Calcium channel blockers, especially verapamil and diltiazem, carry negative inotropic effects and may also bind to amyloid deposits and should be avoided. Angiotensin receptor-neprilysin inhibitors have limited data in amyloidosis and may worsen hypotension. Sodium-glucose cotransporter 2 inhibitors may offer benefits through volume management and cardioprotection, though data remain limited and their use is increasing.

## Key Clinical Pearls

- Cardiac amyloidosis should be suspected in ANY patient > 65 with unexplained LV wall thickening, HFpEF, or low-voltage ECG -- especially if bilateral carpal tunnel syndrome or spinal stenosis preceded cardiac symptoms
- The PYP scan can diagnose ATTR WITHOUT biopsy ONLY if a monoclonal protein workup is completely negative -- this three-test panel (SPEP with immunofixation, UPEP with immunofixation, serum free light chains) MUST be performed before accepting a non-invasive diagnosis
- Tafamidis works best when started EARLY (NYHA I-II) -- the ATTR-ACT trial showed minimal benefit in NYHA III; early diagnosis and treatment are critical to improving outcomes
- Digoxin is absolutely contraindicated in cardiac amyloidosis -- amyloid fibrils avidly bind digoxin, leading to toxicity at standard doses; this is one of the most commonly tested points in cardiology
- The GLS apical sparing pattern is one of the most diagnostically useful echocardiographic findings -- a relative apical longitudinal strain (RALS) > 1.0 has ~90% sensitivity for cardiac amyloidosis and should prompt immediate further workup
- African Americans with HFpEF and LVH should be screened for the V122I TTR mutation (carrier frequency 3-4%) -- this is the most common hereditary ATTR mutation and is treatable with tafamidis and emerging gene silencers

## References

- Kittleson MM, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient with Cardiac Amyloidosis. JACC. 2023;81:1076-1126.
- Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-ACT). NEJM. 2018;379:1007-1016.
- Gillmore JD, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016;133:2404-2412.
- Kastritis E, et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis (ANDROMEDA). NEJM. 2021;385:46-58.
- Garcia-Pavia P, et al. Diagnosis and Treatment of Cardiac Amyloidosis: ESC Position Statement. Eur Heart J. 2021;42:1554-1568.