Cardiac Amyloidosis: How to Diagnose It, the Difference Between ATTR and AL Types, and Why Tafamidis Changes Everything

Research-informed explainer — last updated April 12, 2026

Cardiac amyloidosis — once widely considered an untreatable disease — now has an approved therapy that reduces mortality by 29% in patients with the ATTR form, and a non-invasive diagnostic pathway that avoids biopsy in most cases. The key challenge is recognition: this disease is significantly underdiagnosed, often presenting as "heart failure with preserved ejection fraction" for years before the correct diagnosis is made.

This article draws on research from four cardiologists who have been central to defining this disease. Mazen Hanna, M.D., at Cleveland Clinic, was an author on the landmark ATTR-ACT tafamidis trial and has published extensively on ATTR genotype-phenotype correlations, echocardiographic patterns of cardiac amyloidosis, and the recognition of early warning signs. Sharmila Dorbala, MD, Professor of Radiology and Director of Nuclear Cardiology at Brigham and Women's Hospital, is the senior author on the pivotal 2016 paper establishing a non-biopsy diagnostic algorithm using bone scintigraphy, and co-authored the 2019 expert consensus on ATTR diagnosis. Kevin Alexander, MD, Assistant Professor of Medicine at Stanford Health Care, has published a comprehensive review of AL cardiac amyloidosis and studies on the Val142Ile TTR variant — the most common hereditary ATTR mutation — and its disproportionate impact on patients of African descent. Paul Cremer, M.D., Associate Professor of Medicine at Northwestern Memorial Hospital, is a multimodality cardiac imaging specialist with expertise in distinguishing infiltrative cardiomyopathies.

What is cardiac amyloidosis?

Cardiac amyloidosis occurs when misfolded proteins aggregate into insoluble fibrils and deposit in the heart muscle, causing progressive stiffening (restrictive cardiomyopathy), heart failure, arrhythmias, and conduction disease. The two most clinically relevant types are:

ATTR amyloidosis (transthyretin type): The transthyretin (TTR) protein, primarily produced by the liver, becomes unstable and misfolds. ATTR occurs in two forms:

• Wild-type ATTR (ATTRwt): The protein has a normal gene sequence but becomes unstable with aging. This affects predominantly men over 65 and is far more common than previously recognized.
• Hereditary ATTR (ATTRv): Caused by inherited mutations in the TTR gene. The most common is Val142Ile (V142I), found in approximately 3–4% of African Americans.

AL amyloidosis (light chain type): A plasma cell dyscrasia (related to myeloma) causes overproduction of misfolded immunoglobulin light chains that deposit in the heart and other organs. AL involves the heart in roughly 75% of cases.

A comprehensive review by Hanna and colleagues in the Journal of the American College of Cardiology (2019) synthesized ATTR cardiomyopathy across both forms, detailing the clinical presentation, natural history, and therapeutic options.

How ATTR and AL differ — and why it matters for treatment

The two types are managed completely differently, and confusing them can be dangerous:

Research by Alexander and colleagues has been particularly important for characterizing AL cardiac amyloidosis as a distinct clinical entity, and for understanding outcomes after heart transplantation in amyloidosis patients.

The critical diagnostic step: ruling out AL before treating for ATTR

Before treating a patient as ATTR amyloidosis, AL amyloidosis must be excluded with high confidence. The reason is fundamental: tafamidis does not treat AL, and AL patients who are misdiagnosed and treated as ATTR lose the window for effective plasma cell-directed therapy. Excluding AL requires:

1. Serum free light chain assay
2. Serum protein electrophoresis with immunofixation (SPEP/IFE)
3. Urine protein electrophoresis with immunofixation (UPEP/IFE)

If any of these tests are abnormal, hematology evaluation and tissue biopsy are required to rule out a plasma cell dyscrasia before proceeding.

How to diagnose ATTR without a biopsy

A landmark 2016 study by Dorbala and colleagues, published in Circulation, established a non-invasive diagnostic algorithm that allows ATTR amyloidosis to be diagnosed without cardiac biopsy in most patients. The algorithm relies on technetium pyrophosphate (Tc-PYP) or similar bone scintigraphy scans, which show intense myocardial uptake in ATTR amyloidosis due to the calcium-binding properties of TTR fibrils. The approach:

1. Confirm echocardiographic findings consistent with infiltrative cardiomyopathy (increased wall thickness, preserved EF or mildly reduced EF, diastolic dysfunction)
2. Exclude AL with serum/urine testing (as above)
3. Perform Tc-PYP scan: a Grade 2 or 3 scan (heart uptake equal to or greater than bone) with negative blood and urine immunofixation has a positive predictive value greater than 99% for ATTR amyloidosis

This approach has largely displaced the need for endomyocardial biopsy in ATTR cases, dramatically simplifying the diagnostic pathway for patients.

The 2019 expert consensus by Dorbala and colleagues published in Circulation Heart Failure formalizes these recommendations and provides a practical algorithm that has become the standard of care at amyloid centers.

The red flags: carpal tunnel syndrome and other early signs

One of the most underappreciated aspects of ATTR amyloidosis is that it often gives early warning signs years before cardiac symptoms appear. Research by Hanna and colleagues published in The Journal of Hand Surgery documented that bilateral carpal tunnel syndrome — particularly in older men, especially those requiring surgical release — is a potential red flag for ATTR amyloidosis. Other extracardiac signs include:

• Lumbar spinal stenosis
• Spontaneous biceps tendon rupture
• Lower extremity peripheral neuropathy (in hereditary ATTR)

In one study, up to 14% of patients undergoing carpal tunnel surgery had amyloid deposits in the removed tissue. This creates an opportunity for earlier diagnosis if surgeons and patients recognize the pattern.

The Val142Ile TTR variant, studied by Alexander and colleagues in a 2021 systematic review, is found in approximately 3–4% of African Americans and carries a significantly elevated risk of heart failure and premature death — yet is widely underdiagnosed. The study estimated prevalence among African Americans with heart failure at meaningful levels, reinforcing that race-appropriate screening should be standard practice.

Tafamidis: the treatment that changed outcomes

The ATTR-ACT trial, published in the NEJM in 2018, was a randomized, double-blind trial of 441 patients with ATTR cardiomyopathy (both wild-type and hereditary) treated with tafamidis or placebo for 30 months. Tafamidis is a small molecule that stabilizes the TTR tetramer, preventing it from dissociating into the monomers that misfold and aggregate.

Results were dramatic:

• 29% relative reduction in all-cause mortality in the tafamidis 80 mg group
• 32% reduction in cardiovascular hospitalizations
• Slower decline in 6-minute walk distance
• Slower decline in quality of life scores

Tafamidis was FDA-approved in 2019 under the brand name Vyndaqel (80 mg soft gel capsule). The drug is approved for both wild-type and hereditary ATTR cardiomyopathy in patients with symptomatic disease. It is one of the most expensive cardiovascular drugs available, with annual costs exceeding $225,000, though patient assistance programs exist.

New RNA-based therapies (patisiran, vutrisiran) are approved for hereditary ATTR with polyneuropathy and are being studied in cardiac amyloidosis with encouraging results.

Questions to ask your doctor

• Have I been tested for light chain amyloidosis (AL) to make sure I do not have that type?
• Should I have a Tc-PYP bone scan to evaluate for ATTR amyloidosis?
• Given my African American background, should I be tested for the Val142Ile TTR mutation?
• Do my bilateral carpal tunnel syndrome or biceps tendon issues warrant amyloid evaluation?
• Am I a candidate for tafamidis, and has my heart function been assessed with echocardiography and MRI?
• Is referral to a dedicated cardiac amyloidosis center appropriate for my case?

The bottom line

Cardiac amyloidosis is far more common than once believed and is no longer untreatable. The ATTR-ACT trial established tafamidis as an effective therapy with a 29% mortality reduction over 30 months. A validated non-biopsy diagnostic algorithm using bone scintigraphy can confirm ATTR diagnosis in most cases — but it requires first excluding AL amyloidosis, which is managed completely differently. Early recognition — including awareness of carpal tunnel, biceps tendon rupture, and Val142Ile variant in African Americans — can bring patients to effective treatment years sooner.