Transthyretin Amyloid Cardiomyopathy: Causes, Symptoms, Diagnosis, and Treatments

Learn about transthyretin amyloid cardiomyopathy, its signs, risks, diagnosis, and the latest treatments available.

By Sneha Tete, Integrated MA, Certified Relationship Coach

Created on Sep 26, 2025

Learn about transthyretin amyloid cardiomyopathy, its signs, risks, diagnosis, and the latest treatments available.

Transthyretin Amyloid Cardiomyopathy (ATTR-CM): An In-Depth Guide

Transthyretin amyloid cardiomyopathy, commonly known as ATTR-CM, is a rare and progressive disease defined by the accumulation of abnormally folded transthyretin proteins in the heart tissue. This abnormal protein buildup leads to stiffening of the heart wall, impaired cardiac function, and ultimately heart failure. While ATTR-CM can be difficult to diagnose and is often confused with other cardiac conditions, advances in awareness, diagnostic methods, and treatment options have improved the outlook for many patients.

What is Transthyretin Amyloid Cardiomyopathy?

ATTR-CM is a form of amyloidosis, a broader group of conditions in which abnormal protein deposits (amyloid) accumulate in tissues and organs. In ATTR-CM, the culprit is the transthyretin (TTR) protein, which normally acts as a transporter for thyroid hormone and vitamin A in the blood. When TTR misfolds, it forms insoluble amyloid fibers that accumulate in the heart’s walls, causing them to become rigid and less efficient at pumping blood.

To fully understand the complexities of this condition and the latest advancements in its diagnosis and management, we recommend exploring our comprehensive explainer on ATTR-CM. This resource unravels the specifics of the disease, providing insights that could be vital for patients and caregivers alike.

This process disrupts normal heart function, ultimately resulting in symptoms of heart failure such as shortness of breath, swelling in the legs, and fatigue. The disease can also have systemic effects, with issues arising in the nerves, kidneys, and digestive tract.

Types of ATTR-CM

Hereditary ATTR-CM (hATTR-CM): Caused by mutations in the TTR gene, passed down from parent to child. Sometimes also known as mutated or variant ATTR-CM.
Wild-type ATTR-CM (wtATTR-CM): Results from normal TTR becoming unstable with age, not linked to genetic mutations. Often termed senile systemic amyloidosis.

Other Forms of Transthyretin Amyloidosis

ATTR Amyloidosis Polyneuropathy (ATTR-PN): Primarily affects the peripheral and autonomic nerves, causing nerve-related symptoms including numbness, tingling, and weakness, often alongside cardiac involvement.

To gain a deeper perspective on both types and understand the crucial differences in how each form progresses, check out our detailed FAQ section on ATTR-CM progression. This knowledge will empower you in making informed choices about monitoring and treatment.

What Causes ATTR-CM?

The underlying cause of ATTR-CM is the misfolding of the TTR protein. In its abnormal form, TTR becomes sticky and aggregates into amyloid fibers that are deposited in the heart tissue and other organs.

Hereditary ATTR-CM: Caused by known genetic mutations in the TTR gene. These mutations make the transthyretin molecule less stable and more likely to form amyloid.
Wild-type ATTR-CM: Occurs in people without TTR gene mutations. Here, age and other unknown factors result in native transthyretin becoming unstable, eventually leading to amyloid deposits over time.

Both forms of the disease share similar disease mechanisms but differ in age of onset, familial risk, and the pace of progression.

Who Gets ATTR-CM?

While ATTR-CM is rare, certain groups are at higher risk:

Understanding the potential complications associated with ATTR-CM is imperative. For a more thorough review of these risks, visit our in-depth overview on the complications of transthyretin amyloidosis to stay informed and proactive in your health management.

Wild-type (wtATTR-CM): Typically affects men over age 65, especially those of Caucasian descent.
Hereditary (hATTR-CM): Can affect adults as early as their 50s or 60s. Some genetic variants are more common in specific populations, such as African Americans and people of Portuguese, Swedish, or Japanese descent.
Some rare TTR variants may present earlier or have more aggressive progression, causing symptoms in patients in their 20s–40s.

ATTR-CM is likely underdiagnosed because its symptoms often mimic other forms of heart failure and age-related cardiac issues.

Symptoms and Warning Signs of ATTR-CM

The symptoms of ATTR-CM are diverse and may overlap with other diseases, making diagnosis challenging. The following are the most common presentations:

Life expectancy is a crucial concern for anyone diagnosed with ATTR-CM. To explore essential insights about life expectancy related to ATTR amyloidosis, we encourage you to read our FAQ section, which addresses common concerns and provides valuable information for patients.

Heart failure symptoms: Shortness of breath (especially on exertion), swelling in the legs or abdomen, rapid weight gain from fluid retention, fatigue, and difficulty lying flat due to shortness of breath.
Arrhythmias (irregular heartbeat): Palpitations, lightheadedness, dizziness, or fainting (syncope).
Orthostatic hypotension: A sudden drop in blood pressure when standing up, leading to dizziness or passing out.
Peripheral neuropathy: Tingling, numbness, or weakness in the hands and feet (more common in hereditary forms or polyneuropathy presentations).
Carpal tunnel syndrome: Numbness and tingling in the hands, often preceding cardiac symptoms by years.
Unusual intolerance to common heart failure medications: Some patients report low blood pressure or worsening symptoms after starting beta-blockers or ACE inhibitors.
Other Features: Enlarged heart (cardiomegaly), problems with the kidneys or digestive tract, and, in rare cases, cloudiness or issues in the eyes.

Early Signs That May Be Overlooked

Carpal tunnel syndrome, especially in older adults, can be an early indicator of wild-type ATTR-CM and may even occur a decade or more before cardiac symptoms.
Bilateral biceps tendon rupture is a rare musculoskeletal manifestation that can also precede cardiac involvement.

How is ATTR-CM Diagnosed?

ATTR-CM is often overlooked initially because its symptoms parallel those of other cardiac conditions. Awareness of red flags is essential for timely diagnosis:

Unexplained heart failure with preserved ejection fraction (HFpEF), particularly in older adults.
Heart failure that does not respond as typical to standard therapy.
Presence of neuropathy or carpal tunnel syndrome in a patient with heart symptoms.

Standard Diagnostic Steps

Medical History and Physical Exam: Assess for heart failure, arrhythmias, neuropathy, and musculoskeletal symptoms.
Blood and Urine Tests: To look for signs of amyloid proteins and rule out light-chain (AL) amyloidosis.
Electrocardiogram (ECG): May reveal low voltage signals or arrhythmias atypical for thickened heart.
Echocardiogram: Ultrasound reveals thickened heart walls with ‘speckled’ appearance, reduced motion, and diastolic dysfunction.
Nuclear Imaging: Specialized nuclear scans (pyrophosphate or DPD scintigraphy) can highlight amyloid deposits characteristic of ATTR but not AL amyloidosis.
Cardiac MRI: Provides detailed images of heart structure and detects amyloid infiltration.
Genetic Testing: Critical to distinguish hereditary from wild-type forms, and important for family screening.
Biopsy: In some cases, a heart or other tissue biopsy may be required to confirm ATTR-CM via direct visualization of amyloid deposits.

Managing and Treating ATTR-CM

Until recently, supportive care was the mainstay for patients with ATTR-CM. However, several new options now target the underlying disease process. Early diagnosis is crucial to benefit from these targeted therapies before advanced cardiac damage occurs.

Conventional Supportive Care

Diuretics: To manage fluid retention and relieve symptoms of heart failure.
Management of arrhythmias: Includes medications and, when needed, pacemaker implantation.
Precautions with standard heart failure drugs: Many patients with ATTR-CM do not tolerate ACE inhibitors, beta-blockers, or ARBs due to hypotension or worsening symptoms.
Treat associated neuropathy: Pain control, physical therapy, and medications can help improve quality of life.

Targeted Disease-Modifying Treatments

Tafamidis: The first FDA-approved therapy for ATTR-CM (approved in 2019). This oral agent stabilizes TTR protein, slowing or halting further amyloid buildup, and has been shown to reduce mortality and hospitalizations in clinical trials.
Patisiran, Inotersen: RNA interference (RNAi) or antisense oligonucleotide therapies used mainly for hereditary transthyretin amyloidosis with neuropathy; research is ongoing for their cardiac benefits.
Other agents (under study): Several medications are in trial stages, including gene-silencing and amyloid-clearing agents.

Lifestyle and Monitoring

Regular follow-up with a cardiologist experienced in treating amyloidosis is essential.
Monitor for changes in symptoms, particularly shortness of breath, swelling, or new neurological complaints.
Maintain a heart-healthy diet and manage salt intake to help control fluid retention.
Stay current on vaccinations, including influenza and pneumonia, to reduce risk of infection.

Prognosis: Living With ATTR-CM

Outcomes vary based on the form and stage of disease at diagnosis. Early intervention and proper management can help slow disease progression and improve quality of life. Wild-type ATTR-CM typically progresses over years, whereas some hereditary variants may lead to more rapid decline without treatment.

Many patients are able to maintain physical activity and independence for years after diagnosis, especially with new therapies. Regular monitoring, family screening (for hereditary forms), and supportive care remain central to managing the disease.

Frequently Asked Questions About Transthyretin Amyloid Cardiomyopathy

What is the difference between ATTR-CM and other forms of amyloidosis?

ATTR-CM is specifically caused by misfolded transthyretin protein, whereas other forms, such as AL amyloidosis, are caused by fragments of immunoglobulin light chains. Diagnosis and treatment differ significantly.

Is ATTR-CM hereditary?

It may be: Hereditary ATTR-CM (hATTR-CM) is caused by genetic mutations. Wild-type ATTR-CM is not inherited and occurs with aging.

Can ATTR-CM affect other organs?

Yes. Besides the heart, TTR amyloidosis can affect the peripheral nerves, gastrointestinal tract, kidneys, and eyes, especially in hereditary forms.

How is ATTR-CM treated?

Treatment may include TTR-stabilizing drugs such as tafamidis, supportive care, diuretics for heart failure symptoms, and experimental RNA-based therapies. Early diagnosis improves the chances of better outcomes.

Are there clinical trials available?

Yes, ongoing clinical trials are investigating new gene-silencing treatments and medications to help slow or reverse ATTR-CM progression. Discuss participation with your care team if interested.

Summary Table: ATTR-CM Overview

Type	Cause	Typical Onset	Major Symptoms	Treatment
Hereditary ATTR-CM (hATTR-CM)	Genetic mutation	50s–60s (sometimes earlier)	Heart failure, arrhythmia, neuropathy	Tafamidis, RNA therapies, supportive care
Wild-type ATTR-CM (wtATTR-CM)	Aging, wild-type TTR	65+, more common in men	Heart failure, carpal tunnel, enlarged heart	Tafamidis, supportive care

Key Takeaways

ATTR-CM is a rare cause of heart failure, especially in older adults and those with neuropathy or carpal tunnel syndrome.
Symptoms often overlap with other conditions, leading to underdiagnosis.
New, disease-modifying therapies offer hope for better outcomes, making early recognition crucial.
Both patients and providers should be aware of warning signs and risk factors for ATTR-CM.

References

Author

Sneha TeteBeauty & Lifestyle Writer

Sneha is a relationships and lifestyle writer with a strong foundation in applied linguistics and certified training in relationship coaching. She brings over five years of writing experience to thebridalbox, crafting thoughtful, research-driven content that empowers readers to build healthier relationships, boost emotional well-being, and embrace holistic living.

Read full bio of Sneha Tete