Cardiac Amyloidosis

By Edward Aldrich
Medical Officer, MBCHB
Stellenbosch University,
South Africa

Amin H. Karim MD
Baylor College Of Medicine,
Methodist Academic Institute.
Houston, Texas

Patient is a 70-year-old African American male known with atrial fibrillation, hypertension, GERD, venous insufficiency, sleep apnea and benign prostatic hyperplasia, who presented with heart failure due to hypertrophic cardiomyopathy. The diagnosis of transthyretin cardiac amyloidosis was confirmed on biopsy, after suggestive features were seen on echocardiogram and cardiac magnetic resonance.

Epidemiology – Cardiac amyloidosis is a rare form of cardiomyopathy and approximately 95 percent of cases are caused by the deposition of transthyretin (ATTR amyloidosis) or immunoglobulin light chains (AL amyloidosis).

Classification of amyloidosis is based upon the type of precursor protein:

• Transthyretin amyloidosis (ATTR amyloidosis) – Transthyretin amyloidosis results from the misfolding and deposition of transthyretin (TTR, formerly known as prealbumin), a tetrameric protein synthesized by the liver that normally transports vitamin A and thyroid hormone. ATTR amyloidosis can be further divided into two subtypes:

• Wild-type amyloidosis (wtATTR amyloidosis) – Wild-type transthyretin amyloidosis (previously known as senile systemic amyloidosis) is caused by the deposition of misfolded wild-type (normal) transthyretin.
• Hereditary amyloidosis (hATTR amyloidosis) – Hereditary transthyretin amyloidosis is caused by gene mutations in the transthyretin gene (TTR) that lead to abnormal transthyretin formation. The typical transmission of hATTR is autosomal dominant inheritance with variable penetrance, and there are more than 120 known mutations of TTR associated with hATTR amyloidosis.
• Light chain amyloidosis (AL amyloidosis) – Light chain amyloidosis (AL amyloidosis; also known as primary systemic amyloidosis) results from deposition of misfolded immunoglobulin light chains from a plasma cell dyscrasia.
• Other types of amyloid – Rare causes of cardiac amyloidosis include serum amyloid A amyloidosis, hereditary apolipoprotein A-1, and apolipoprotein A-4 amyloidosis.

Clinical manifestations – The clinic phenotype varies, and an often-generic clinic presentation makes it difficult to establish a diagnosis.

Presentations at age ≥60 years are most common. Each transthyretin mutation is associated with its own age range (from 30 to 70 years) and the particular risk for cardiomyopathy varies. The main manifestations of ATTR amyloidosis are cardiac.

Electrocardiogram – Discordance between increased left ventricular wall thickness (on cardiac imaging ie echocardiography) and QRS voltage, which is often reduced, is the classic sign of cardiac amyloidosis. However, this has low sensitivity, and the prevalence of low voltage shows significant variation, depending on the cause, with less frequency in patients with ATTR amyloidosis (20 percent) than in patients with AL amyloidosis (60 percent).

When to suspect cardiac amyloidosis – Cardiac amyloidosis should be suspected in patients with:

• Unexplained LV hypertrophy (with or without heart failure [HF]).
• Aortic stenosis with features associated with cardiac amyloidosis (such as presence of low-flow, low-gradient aortic stenosis and/or echocardiographic detection of impaired longitudinal strain [eg, mitral annular S’ ≤6 m/sec]).
• Symptoms or signs typical of AL or ATTR amyloidosis and HF.
• A condition highly associated with cardiac amyloidosis (eg, systemic AL amyloidosis, ATTR-related peripheral neuropathy, or ATTR mutation carrier state).

Diagnosis – For patients with any of the above features, cardiovascular magnetic resonance (CMR) imaging is recommended.

• If CMR findings suggest cardiac amyloidosis, testing for evidence of monoclonal protein using serum protein immunofixation, urine protein immunofixation, and serum free light chain ratio analysis is the next step.
• If monoclonal protein is identified, hematology referral, tissue biopsy and bone marrow biopsy are indicated.
• If monoclonal protein is not identified, further evaluation is based upon the results of bone tracer cardiac scintigraphy.
• If CMR is not suggestive of cardiac amyloidosis, cardiac amyloidosis is unlikely and other causes of LVH and/or HF should be considered.

Treatment of specific complications of cardiac amyloidosis

• Atrial fibrillation
  • Rate and rhythm control – In patients with atrial fibrillation, rate control should be prioritized over rhythm control. For most patients, amiodarone is recommended for rate control. In patients in whom amiodarone is not an option for therapy, low-dose digoxin or low-dose beta blockers are alternatives.
  • Anticoagulation – In patients with cardiac amyloidosis and atrial fibrillation or atrial flutter, anticoagulation is recommended. Standard risk estimators (eg, CHA₂DS₂VASC) are not validated in amyloidosis.
  • Cardioversion – In patients with AL or ATTR cardiac amyloidosis who require cardioversion for symptomatic management, transesophageal echocardiography (TEE) is recommended prior to cardioversion rather than no transesophageal echocardiography prior to cardioversion. This is to exclude the presence of emboli.
• Conduction system disease – In patients with cardiac amyloidosis, general indications for cardiac pacing are recommended.

Specific treatment for ATTR amyloidosis

Medical therapy – In patients with ATTRwt or ATTRv (where “v” indicates “variant”) cardiac amyloidosis and New York Heart Association (NYHA) functional class I to III HF symptoms, tafamidis is recommended rather than no disease specific therapy, and tafamidis is preferrable to diflunisal. Diflunisal is poorly tolerated and has unclear efficacy in patients with cardiac amyloidosis.

Therapy for heart failure – In patients with ATTR cardiac amyloidosis with either HFrEF (HF with reduced ejection fraction) or HFpEF (HF with preserved ejection fraction), there are no specific recommendations for HF therapy other than general HF treatment measures and diuretics for volume overload.

In patients with refractory HF, therapeutic options include palliative care, heart transplantation, mechanical circulatory support, and continuous inotrope infusion.

Liver transplantation – This only has proven benefit for patients with familial amyloid polyneuropathy. Potential benefit for cardiac amyloidosis is controversial.

Prognostic indicators

• The first published staging system for patients with ATTRwt cardiac amyloidosis is based on serum levels of NT-proBNP and cardiac troponin T.
• The second staging system, validated in patients with ATTRwt or ATTRv, is based on serum levels of NT-proBNP and eGFR.

Adapted from the following UpToDate articles:

• Cardiac amyloidosis: Epidemiology, clinical manifestations, and diagnosis by Marianna Fontana, MD
• Cardiac amyloidosis: Treatment and prognosis by Marianna Fontana, MD