Amyloid Cardiomyopathy (Cardiomyopathy of Transthyretin-Mediated Amyloidosis)

Amyloid Cardiomyopathy (Transthyretin-Mediated) – Treatment Overview

Introduction
Amyloid cardiomyopathy (ATTR-CM) is a restrictive cardiomyopathy caused by deposition of misfolded transthyretin (TTR) protein in the myocardium. TTR is a liver-derived protein that normally transports thyroxine and retinol-binding protein. Misfolding leads to amyloid fibril deposition, stiffening the heart, impaired diastolic filling, arrhythmias, and ultimately heart failure.

There are two major forms:

• Hereditary ATTR (hATTR): Caused by mutations in the TTR gene.

• Wild-type ATTR (wtATTR): Age-related, without mutation; more common in older men.

Early diagnosis is critical because disease-modifying therapies can slow progression but not reverse existing damage.

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Disease-Modifying Therapies

1. TTR Stabilizers

• Tafamidis (first-line):

  • Dose: 61 mg orally once daily.

  • Mechanism: Stabilizes TTR tetramer, preventing dissociation into monomers that misfold into amyloid fibrils.

  • Shown to reduce mortality and cardiovascular hospitalizations in ATTR-ACT trial.

• Diflunisal (off-label, NSAID):

  • Dose: 250 mg orally twice daily.

  • Stabilizes TTR tetramers, but limited by NSAID toxicity (renal, GI, cardiac).

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2. Gene Silencers (RNA-based therapies, mainly for hATTR)

• Patisiran (siRNA):

  • Dose: 0.3 mg/kg IV infusion every 3 weeks.

  • Reduces hepatic production of TTR. Approved for hATTR polyneuropathy; cardiac benefit also demonstrated.

• Inotersen (antisense oligonucleotide):

  • Dose: 284 mg subcutaneous weekly.

  • Also reduces TTR synthesis. Requires monitoring for thrombocytopenia and renal toxicity.

• Vutrisiran (next-gen siRNA):

  • Dose: 25 mg subcutaneous every 3 months.

  • Long-acting, well tolerated, effective in both neuropathy and cardiomyopathy.

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3. Investigational / Advanced Therapies

• CRISPR-based therapies (NTLA-2001): In clinical trials; aims for permanent knockdown of TTR gene expression.

• Liver transplantation: Rarely performed now, historically used in hereditary ATTR.

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Supportive / Symptomatic Management

Heart Failure Management (restrictive phenotype)

• Diuretics (loop diuretics like furosemide): For volume overload; use cautiously to avoid hypotension.

• Mineralocorticoid receptor antagonists: May be used in selected patients.

• Avoid: Beta-blockers, ACE inhibitors, ARBs – often poorly tolerated due to low blood pressure and autonomic dysfunction.

Arrhythmia Management

• Atrial fibrillation is common → anticoagulation recommended (high thromboembolic risk).

• Pacemaker implantation if significant conduction disease.

• ICD use is controversial (sudden cardiac death often due to electromechanical dissociation).

Other Supportive Care

• Salt restriction, fluid balance monitoring.

• Management of neuropathy in hereditary ATTR with neuropathic pain agents if present.

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Prognosis

• Without treatment, median survival is 2–6 years after heart failure onset.

• Tafamidis and RNA-silencing therapies significantly improve survival and functional outcomes, especially if started early.