Understanding Transthyretin Amyloid Cardiomyopathy (ATTR-CM)
Explore the causes, symptoms, diagnosis, treatment, and living strategies for transthyretin amyloid cardiomyopathy (ATTR-CM).
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive condition in which abnormal protein deposits—called amyloids—build up in the heart muscle, resulting in reduced heart function and heart failure. This article provides a comprehensive overview of ATTR-CM, including its forms, causes, risk factors, symptoms, diagnostic process, treatment approaches, and strategies for living with the disease.
What is Transthyretin Amyloid Cardiomyopathy?
ATTR-CM is a rare type of restrictive cardiomyopathy—or heart muscle disease—caused by the accumulation of amyloid fibrils formed from misfolded transthyretin (TTR) proteins within the heart. These deposits stiffen the heart muscle, making it harder for the heart to pump blood and leading to congestive heart failure over time.
TTR is a protein naturally produced in the liver that normally transports thyroid hormone and vitamin A. When TTR proteins misfold and aggregate, they can deposit in various organs—most notably the heart and nerves—disrupting normal tissue function. The specific involvement of the heart distinguishes ATTR-CM as a subset of amyloidosis focused on cardiac pathology.
Types of ATTR-CM
There are two principal types of transthyretin amyloid cardiomyopathy:
- Wild-type ATTR-CM (wtATTR-CM): This form results from the age-related misfolding of normal TTR proteins. It primarily affects older adults, often men over the age of 65, and is not associated with genetic mutations.
- Hereditary or variant ATTR-CM (hATTR-CM): This form is caused by inherited mutations in the TTR gene. It can present as early as in the 30s or 40s but more commonly begins in people in their 50s or 60s. More than 120 TTR mutations have been identified, leading to different clinical manifestations and age of onset.
ATTR-CM vs. Other Forms of Amyloidosis
There are several types of amyloidosis, but in ATTR-CM, the amyloid is specifically made of misfolded TTR proteins. Other forms, such as AL (light-chain) amyloidosis, involve different proteins and present distinct clinical challenges and treatments.
Causes and Risk Factors
The two primary causes of ATTR-CM are aging (for wtATTR-CM) and genetic mutations (for hATTR-CM).
- Aging: Wild-type ATTR-CM occurs as a result of the destabilization and misfolding of otherwise normal TTR proteins, typically in people over age 65.
- Genetics: Hereditary ATTR-CM is linked to specific TTR gene mutations inherited from one or both parents. Different mutations can affect the disease’s age of onset and severity.
Other notable risk factors include:
- Male sex (particularly for wild-type ATTR-CM)
- Family history of amyloidosis or unexplained heart failure
- Ethnic background (some mutations are more common in certain populations, such as the V122I mutation in people of African descent)
- Previous diagnosis of carpal tunnel syndrome, biceps tendon rupture, or spinal stenosis, particularly in older adults
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Symptoms of ATTR-CM
Symptoms of ATTR-CM overlap with those of other forms of heart failure and can be subtle or misattributed to other causes, especially in older adults. As amyloid buildup progresses, the symptoms generally worsen.
- Shortness of breath, especially with exertion or when lying flat
- Fatigue and decreased exercise tolerance
- Swelling in the legs, ankles, feet, or abdomen
- Heart palpitations or irregular heartbeats (arrhythmias, such as atrial fibrillation)
- Lightheadedness or dizziness, sometimes leading to fainting
- Sudden drop in blood pressure upon standing (orthostatic hypotension)
- Numbness or tingling in the hands and feet (if amyloid affects nerves)
- Carpal tunnel syndrome, especially if both wrists are involved
Symptoms related to nerve or other organ involvement may also occur, especially in hereditary ATTR (hATTR-CM), including gastrointestinal disturbances, unintentional weight loss, or autonomic dysfunction (affecting blood pressure, digestion, etc.).
Pathophysiology: How ATTR-CM Develops
ATTR-CM develops when TTR proteins misfold and aggregate into insoluble amyloid fibrils. These deposits accumulate within the heart’s interstitial spaces, particularly in the walls of the ventricles, making the myocardium stiff and hypertrophied.
- The thickened heart muscle reduces the heart’s ability to relax and fill—a condition called diastolic dysfunction, which can progress to systolic dysfunction as the disease advances.
- Increased pressure in the heart chambers can cause atrial enlargement, raising the risk for arrhythmias, most notably atrial fibrillation.
- Amyloid deposits can affect the heart’s conduction system, leading to bradycardia (slow heart rate) or heart block.
In hereditary forms, amyloid deposition can also occur outside the heart, in the peripheral and autonomic nerves as well as other organs.
Diagnosis of ATTR-CM
Diagnosing ATTR-CM is challenging, as its symptoms mimic those of more common heart conditions. Timely and accurate diagnosis is critical because treatments can help slow disease progression, but may not reverse damage.
Diagnostic Steps
- Clinical evaluation: A thorough medical history, including family history and symptoms suggestive of nerve involvement, is essential.
- Echocardiogram: Imaging can reveal thickened ventricular walls and characteristic changes in heart function.
- Cardiac MRI: Provides detailed images of the heart muscle and can highlight abnormal tissue composition.
- Nuclear imaging (bone scintigraphy): Isotope tracers can indicate amyloid deposits specific to ATTR-CM.
- Blood and urine tests: Help exclude AL amyloidosis and check for abnormal TTR protein levels or other systemic involvement.
- Genetic testing: Used to identify mutations in the TTR gene and differentiate hATTR-CM from wtATTR-CM.
- Biopsy: In some cases, a tissue sample from the heart or another affected organ is required to identify amyloid deposits and confirm the diagnosis.
Treatment Options for ATTR-CM
Treatment strategies for ATTR-CM focus on slowing disease progression, managing heart failure symptoms, and addressing complications. Until recently, management options were mostly limited to supportive care, but new disease-modifying therapies have become available.
FDA-Approved Medications
- Tafamidis: The first FDA-approved oral therapy for ATTR-CM, tafamidis stabilizes the TTR protein, preventing it from misfolding and forming amyloid deposits. Tafamidis has been shown to reduce mortality and cardiovascular-related hospitalizations but does not reverse existing amyloid deposits.
- Patisiran and inotersen: Approved for treating neuropathy associated with hereditary ATTR, these drugs work by decreasing the liver’s production of TTR protein and are being studied for use in ATTR-CM.
- Other investigational agents: Drugs that degrade or promote the clearance of amyloid fibrils are under investigation in clinical trials.
Symptom Management
- Diuretics: Help manage fluid retention and swelling.
- Arrhythmia management: Beta-blockers and calcium channel blockers are often poorly tolerated. Pacemaker implantation may be needed to address conduction issues.
- Avoidance of certain heart failure medications: Standard drugs such as ACE inhibitors or angiotensin receptor blockers, and beta-blockers, may cause severe low blood pressure and are often poorly tolerated in ATTR-CM.
Lifestyle and Supportive Measures
- Diet: Low-sodium diet helps control swelling and heart failure symptoms.
- Physical activity: Light to moderate exercise as tolerated can improve endurance but should be tailored to current abilities.
- Multidisciplinary care: Collaboration with heart failure specialists, neurologists, and genetic counselors is critical, especially for those with hereditary forms.
Living with ATTR-CM
An ATTR-CM diagnosis can be life-changing, but with appropriate care and a proactive approach, many people can maintain their independence and quality of life. Here are some key strategies:
- Regular follow-up: Work closely with your healthcare team to monitor disease progression and manage complications.
- Symptom tracking: Keep a diary of symptoms such as weight changes, swelling, palpitations, and overall energy levels.
- Education and support: Join patient support groups and seek information about recent advancements.
- Family screening: In hereditary ATTR-CM, genetic counseling and family testing can help identify at-risk relatives early.
- Vaccinations: Stay up-to-date with vaccination for flu and pneumonia to reduce risk of infection.
Frequently Asked Questions (FAQs)
What is the difference between hereditary and wild-type ATTR-CM?
Hereditary ATTR-CM is caused by mutations in the TTR gene and may present earlier in life, often with both cardiac and neurologic involvement. Wild-type ATTR-CM occurs in older adults without genetic mutations and primarily affects the heart.
Can ATTR-CM be cured?
There is currently no cure for ATTR-CM. However, recent advances—most notably tafamidis—can slow progression and reduce symptoms. Ongoing research is focused on new therapies that may further improve outcomes.
How is ATTR-CM different from traditional heart failure?
ATTR-CM is caused by amyloid protein deposits in the heart, which leads to a stiffer and less efficient heart muscle. Typical heart failure treatments are often not effective, and some may be poorly tolerated in ATTR-CM patients.
Who is at risk for developing ATTR-CM?
Older adults, especially men, are at highest risk for wild-type ATTR-CM. Those with a family history of amyloidosis or unexplained heart failure—particularly of African or Irish descent—may have an increased risk of hereditary ATTR-CM.
What should I do if I suspect I have ATTR-CM?
Consult a cardiologist or heart failure specialist who is familiar with amyloidosis. Diagnosis may require specialized tests, imaging, and possibly genetic evaluation.
Summary Table: ATTR-CM Overview
| Aspect | Description |
|---|---|
| Type | Wild-type (wtATTR-CM), Hereditary (hATTR-CM) |
| Major Risk Factors | Age (over 65), Genetic Mutations, Male Sex |
| Main Symptoms | Heart failure, swelling, arrhythmias, neuropathy |
| Key Diagnostic Tools | Echocardiogram, Cardiac MRI, Nuclear imaging, Genetic Testing, Biopsy |
| Treatment | Tafamidis, diuretics, symptom management, supportive care |
| Outlook | Progressive, treatable but not curable; early intervention improves outcomes |
Additional Resources
- Amyloidosis Foundation: Advocacy and patient education resources
- Heart Failure Societies: Up-to-date guidelines on diagnosis and management
- Genetic counseling services: For families affected by hereditary amyloidosis
References
- https://www.ncbi.nlm.nih.gov/books/NBK574531/
- https://www.pfizer.com/news/articles/understanding_this_rare_disease_called_attr_amyloidosis
- https://www.uhhospitals.org/services/heart-and-vascular-services/conditions-and-treatments/cardiomyopathy/transthyretin-amyloid-cardiomyopathy
- https://my.clevelandclinic.org/health/diseases/17855-amyloidosis-attr
- https://www.heart.org/en/health-topics/cardiomyopathy/what-is-cardiomyopathy-in-adults/transthyretin-amyloid-cardiomyopathy-attr-cm
- https://www.mayoclinic.org/diseases-conditions/amyloidosis/symptoms-causes/syc-20353178
- https://hfsa.org/heart-failure-and-attr-cm-why-early-detection-matters
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