Cardiac Amyloidosis

Table of Contents

  1. Overview
  2. AL vs ATTR: The Two Main Types
  3. Pathophysiology
  4. Clinical Presentation
  5. ECG, Echocardiography, and Cardiac MRI
  6. Tc-99m Pyrophosphate Scan for ATTR
  7. Biopsy and Histologic Confirmation
  8. Treatment: Tafamidis, Gene Silencers, and Supportive Care
  9. Prognosis and Monitoring
  10. Research Papers
  11. Connections
  12. Featured Videos

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1. Overview

Cardiac amyloidosis is a form of infiltrative cardiomyopathy caused by the deposition of misfolded protein fibrils — collectively called amyloid — in the myocardium, conduction system, valves, and coronary vessels. These insoluble fibrils are rigid and do not contract; their accumulation stiffens the ventricular walls, impairs diastolic relaxation, and progressively disrupts electrical conduction. The result is a restrictive cardiomyopathy phenotype: thick, non-compliant walls with a small or normal-sized ventricular cavity and severely elevated filling pressures despite preserved or only mildly reduced ejection fraction.

Cardiac amyloidosis has historically been underdiagnosed and was considered rare. The development of highly sensitive non-invasive diagnostic tools — particularly the Tc-99m pyrophosphate (PYP) nuclear scan — and the approval of disease-modifying therapy (tafamidis) in 2019 have transformed the field. It is now recognized that wild-type ATTR amyloidosis is far more prevalent than previously appreciated, particularly in men over 65 presenting with heart failure with preserved ejection fraction (HFpEF).

Over 30 different proteins can misfold to form amyloid, but the two clinically dominant forms affecting the heart are:

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2. AL vs ATTR: The Two Main Types

AL (Light-Chain) Amyloidosis

AL amyloidosis is caused by a clonal proliferation of plasma cells (or, rarely, B-cell lymphoma) that produce excess immunoglobulin free light chains (predominantly lambda over kappa, in a 3:1 ratio). These light chains misfold and form amyloid fibrils that deposit in multiple organs, with the heart, kidneys, liver, and peripheral nerves being the most commonly affected.

ATTR (Transthyretin) Amyloidosis

Transthyretin (TTR) is a homotetrameric protein produced primarily by the liver. It normally dissociates into monomers that misfold and aggregate into amyloid fibrils. ATTR amyloidosis has two subtypes:

Wild-Type ATTR (ATTRwt) — Senile Cardiac Amyloidosis

Hereditary/Variant ATTR (ATTRv) — Familial Amyloid Cardiomyopathy

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3. Pathophysiology

Amyloid fibrils infiltrate all layers of the myocardium — predominantly the interstitium between cardiomyocytes — and the subendocardial regions. The mechanical consequences include:

Restrictive Physiology

The hallmark of cardiac amyloidosis is restrictive cardiomyopathy: the ventricles are thick, stiff, and non-compliant. They can fill only at very high pressures. This manifests as:

Conduction System Involvement

Amyloid infiltration of the atrioventricular (AV) node and His-Purkinje system causes:

Autonomic Neuropathy (especially ATTRv)

In hereditary ATTR, amyloid deposits in autonomic nerves cause orthostatic hypotension, GI dysmotility (diarrhea/constipation alternation), bladder dysfunction, and sexual dysfunction — symptoms that often precede cardiac manifestations by years.

Direct Amyloid Toxicity

Beyond mechanical stiffening, soluble amyloid oligomers (pre-fibrillar forms) are directly cytotoxic to cardiomyocytes via oxidative stress and mitochondrial dysfunction — particularly relevant in AL amyloidosis, where light chain oligomers cause acute cardiomyocyte injury disproportionate to the fibril burden.

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4. Clinical Presentation

Heart Failure Symptoms

Cardiac amyloidosis presents as progressive heart failure with:

Extra-Cardiac Clues

Physical Examination

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5. ECG, Echocardiography, and Cardiac MRI

Electrocardiogram (ECG)

The ECG in cardiac amyloidosis shows a pattern that is almost paradoxical — and highly characteristic:

Echocardiography

Echocardiography reveals the structural consequences of infiltration:

Cardiac MRI

Cardiac magnetic resonance imaging (CMR) with gadolinium contrast provides the most sensitive and specific imaging findings:

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6. Tc-99m Pyrophosphate Scan for ATTR

The Tc-99m pyrophosphate (PYP) bone scan has emerged as a non-invasive diagnostic breakthrough for ATTR cardiac amyloidosis. This nuclear medicine test, originally used for bone scanning, demonstrates avid uptake in ATTR-deposited myocardium — thought to reflect calcium binding to amyloid fibrils. Importantly, it is specific for ATTR and does not significantly label AL amyloid.

Technique and Interpretation

Diagnostic Performance

When interpreted correctly (with SPECT and after excluding AL amyloidosis via serum free light chains + immunofixation electrophoresis):

Practical Workflow

  1. Serum free light chains + serum immunofixation electrophoresis + urine immunofixation electrophoresis — rule out AL
  2. Tc-99m PYP SPECT/planar scan
  3. If PYP positive + AL excluded: ATTR confirmed. TTR gene sequencing distinguishes wild-type from variant.
  4. If PYP negative + clinical suspicion high: myocardial biopsy required

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7. Biopsy and Histologic Confirmation

Tissue biopsy with Congo red staining remains the gold standard for amyloid confirmation. Amyloid fibrils produce pathognomonic apple-green birefringence under polarized light after Congo red staining. Typing (distinguishing AL from ATTR) requires further analysis by immunohistochemistry, immunofluorescence, or mass spectrometry proteomic analysis (the most accurate method, available at amyloid referral centers).

Biopsy Sites

Amyloid Typing

Accurate subtype determination is critical because treatment differs entirely between AL and ATTR. Mass spectrometry-based proteomics on formalin-fixed paraffin-embedded tissue is now the reference standard for typing and can identify the specific precursor protein from any tissue specimen. Immunohistochemistry is less accurate and may mistype, particularly with rare TTR variants.

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8. Treatment: Tafamidis, Gene Silencers, and Supportive Care

Tafamidis (ATTR-CM): Disease-Modifying Therapy

Tafamidis (Vyndamax/Vyndaqel, Pfizer) is the first approved disease-modifying therapy for ATTR cardiomyopathy. It is a small-molecule TTR tetramer stabilizer — it binds the TTR tetramer at the thyroxine-binding sites, preventing tetramer dissociation into the amyloidogenic monomers.

TTR Gene Silencers (Hereditary ATTR)

For ATTRv (hereditary ATTR), therapies that reduce hepatic TTR production dramatically lower circulating amyloidogenic TTR:

AL Amyloidosis: Anti-Plasma Cell Therapy

Treatment of AL amyloidosis is directed at suppressing the underlying clonal plasma cells to eliminate light chain production:

Supportive Heart Failure Management

Standard heart failure medications require modification in cardiac amyloidosis:

Heart Transplantation

Cardiac transplantation is considered for selected patients with AL amyloidosis who achieve complete hematologic response (preventing re-deposition in the graft) and for select ATTRv patients. Combined liver + heart transplantation (liver produces TTR) is performed at specialized centers for ATTRv patients with severe cardiomyopathy. Results at experienced centers are comparable to transplantation for other cardiomyopathies.

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9. Prognosis and Monitoring

Prognostic Staging

AL amyloidosis — Mayo 2012 Staging System:

ATTR cardiac amyloidosis — NAC staging:

Monitoring on Therapy

Overall Outlook

The prognosis of cardiac amyloidosis has improved substantially with the availability of tafamidis and gene silencers. ATTRwt patients treated with tafamidis now have median survival approaching 4–6 years from diagnosis, compared to 2–3 years historically. ATTRv patients treated with gene silencers and tafamidis can have disease stabilization or even modest improvement. AL amyloidosis prognosis depends heavily on achieving rapid, deep hematologic response — patients who reach a complete hematologic response have near-normal long-term survival in some series.

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Research Papers

The following PubMed citations represent landmark and recent literature on cardiac amyloidosis. Each link opens the abstract or full text.

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Connections

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