ATTR-CM (transthyretin amyloid cardiomyopathy) is a progressive heart condition caused by a misfolded protein called transthyretin that deposits in the heart muscle, making it stiff and impairing its ability to pump blood. It’s increasingly recognized as an underdiagnosed cause of heart failure, particularly in adults over 65. Screening studies suggest that roughly 6% of patients with heart failure and thickened heart walls actually have ATTR-CM that hasn’t been identified.
How the Disease Develops
Transthyretin (TTR) is a protein made primarily by the liver. Its normal job is to carry thyroid hormone and vitamin A through the bloodstream. In its healthy state, TTR exists as a stable unit of four identical protein chains bound together (a tetramer). In ATTR-CM, those four chains fall apart into individual pieces that then misfold into abnormal shapes.
These misfolded proteins don’t just float harmlessly. They clump together into rigid, thread-like fibers called amyloid fibrils, which accumulate in the heart muscle over time. Once lodged in heart tissue, the amyloid deposits trigger programmed cell death in heart muscle cells and cause progressive scarring and stiffening. The result is a heart that can’t relax properly between beats, leading to diastolic dysfunction, meaning the heart struggles to fill with blood. The deposits also disrupt the heart’s electrical system, causing rhythm abnormalities like atrial fibrillation.
Two Types: Wild-Type and Hereditary
ATTR-CM comes in two forms, depending on what causes the protein to misfold.
Wild-type ATTR-CM (wtATTR) occurs when the TTR protein begins misfolding on its own without any genetic cause. This is linked to aging-related changes in protein stability and typically affects people over 65. It predominantly affects men, though clinicians now recognize it was likely underdiagnosed in women for years.
Hereditary ATTR-CM (hATTR) is caused by inherited mutations in the TTR gene. Over 120 different gene variants have been linked to this form. The most clinically significant mutation in the United States is called Val122Ile (V122I), carried by 3% to 4% of Black Americans. Hereditary ATTR-CM can appear earlier in life depending on the specific mutation, and it sometimes affects the nerves in addition to the heart.
Early Warning Signs That Appear Years Before
One of the most important things to know about ATTR-CM is that the body often sends signals long before heart failure symptoms appear. Amyloid deposits don’t just accumulate in the heart. They also build up in joints, tendons, and the tissue surrounding nerves. These musculoskeletal problems can precede a cardiac diagnosis by years.
Carpal tunnel syndrome is the most common early sign, found in up to 87% of ATTR-CM patients. It can appear up to 12 years before the heart condition is diagnosed. Other red flags include trigger finger, unexplained tears of the biceps tendon or rotator cuff (without a clear injury), spinal stenosis, and large joint arthritis. These often show up individually or in clusters, particularly in men over 60. When an older adult has bilateral carpal tunnel syndrome alongside unexplained heart thickening or heart failure, ATTR-CM should be on the radar.
How ATTR-CM Is Diagnosed
Diagnosis has become dramatically easier in recent years thanks to a noninvasive imaging test called a bone scintigraphy scan (often using a tracer called technetium pyrophosphate, or PYP). This scan was originally designed for bone imaging, but it turns out that the radioactive tracer binds strongly to the type of amyloid found in ATTR-CM.
Results are graded on a scale of 0 to 3, known as the Perugini grading system. Grade 0 means no heart uptake. Grade 1 means mild uptake, less intense than the bone signal. Grade 2 means the heart lights up as brightly as, or brighter than, the bones. Grade 3 means the heart signal is so intense that bone uptake is barely visible. A grade 2 or 3 result has a 100% positive predictive value for ATTR-CM, as long as a separate blood and urine test has first ruled out a different type of amyloidosis called AL amyloidosis (caused by abnormal immune cells rather than TTR).
If that blood screening for AL amyloidosis comes back abnormal, a tissue biopsy becomes necessary to determine exactly which type of amyloid is present. A biopsy of an easily accessed site like abdominal fat has low sensitivity, so a negative result from that location doesn’t rule anything out, and a direct heart biopsy may sometimes be needed. Genetic testing is also recommended to distinguish wild-type from hereditary forms, since the hereditary type has implications for family members.
Treatment With TTR Stabilizers
The first major breakthrough in ATTR-CM treatment came with tafamidis, a drug that works by binding to the TTR protein and holding the four-chain structure together, preventing it from falling apart and misfolding. In the landmark ATTR-ACT clinical trial, tafamidis produced a 13.4% absolute reduction in overall mortality and a 22% absolute reduction in cardiovascular hospitalizations per year over 30 months compared to placebo.
Real-world data from a large patient registry has confirmed these benefits outside of a controlled trial setting. Survival rates at 30 months were about 84% in patients treated with tafamidis versus 70% in untreated patients. At 42 months, that gap widened further: roughly 77% survival in treated patients compared to 59% in those who were untreated. These patterns held across both wild-type and hereditary forms of the disease.
Newer Therapies That Reduce TTR Production
While tafamidis stabilizes the protein, a newer class of treatment takes a different approach: stopping the liver from making so much TTR in the first place. Vutrisiran, a gene-silencing therapy given as a subcutaneous injection once every three months, reduces TTR production at its source.
The HELIOS-B trial tested vutrisiran specifically in patients with ATTR-CM and found that it reduced the risk of death from any cause by 36% and cardiovascular death by 33% over 42 months of follow-up. Heart failure hospitalizations dropped by 33%, and urgent heart failure visits were cut nearly in half. These results represent a meaningful step forward, particularly for patients who may benefit from combining TTR reduction with stabilization.
Living With ATTR-CM
ATTR-CM is a chronic, progressive condition, but the outlook has improved substantially with available therapies. Standard heart failure management, including careful fluid balance and treatment of arrhythmias like atrial fibrillation, remains important alongside disease-specific drugs. Some common heart failure medications like beta-blockers and ACE inhibitors are poorly tolerated in ATTR-CM because the stiff heart relies on a faster heart rate and higher filling pressures to maintain output, so medication adjustments often differ from typical heart failure care.
Because early treatment produces better outcomes, the biggest challenge is still getting diagnosed in time. If you’ve been told you have heart failure with a thick heart muscle, particularly if you’re over 65 or have a history of bilateral carpal tunnel syndrome, asking about ATTR-CM screening with a pyrophosphate scan is a reasonable and increasingly accessible step.