Sharmila Dorbala, MD, MPH, MASNC

Diagnostic Approach to ATTR-CM

Summary for Physicians: Diagnostic Approach and Challenges in ATTR-CM

 Early recognition is critical, particularly in patients with unexplained heart failure, arrhythmias, or extracardiac symptoms such as carpal tunnel syndrome, spinal stenosis, and trigger fingers.

 Identifying mutations in the transthyretin (TTR) gene can confirm hereditary transthyretin amyloid cardiomyopathy (ATTR-CM).

 Elevated NT-proBNP and cardiac troponins can suggest cardiac involvement.

 These imaging techniques help identify signs of restrictive cardiomyopathy, abnormal left ventricular wall thickness, and amyloid deposits.

 In some cases, a biopsy (eg, from fat or cardiac tissue) may be performed to confirm amyloid deposition through Congo red staining.

 Technetium-labeled imaging agents, such as bone scintigraphy, can be used to detect cardiac amyloid deposits.

 ATTR-CM is often misdiagnosed as other forms of heart failure or restrictive cardiomyopathy. It may be mistaken for conditions such as hypertension, coronary artery disease, or idiopathic heart failure, especially in older patients.

 The slow progression of symptoms and their overlap with more common conditions lead to a significant delay in diagnosis. This can result in advanced disease before appropriate treatment is initiated.

 A late diagnosis can result in worsening heart failure, arrhythmias, and irreversible organ damage, leading to a poor prognosis and diminished quality of life.

 Progressive symptoms such as heart failure, arrhythmias, and extracardiac manifestations (eg, carpal tunnel syndrome, trigger fingers) can severely affect daily activities, mobility, and overall well-being.

 The uncertainty due to delayed diagnosis can cause anxiety and frustration for both patients and caregivers.

Early and accurate diagnosis is essential to improving patient outcomes, providing appropriate treatments, and enhancing the patient’s quality of life.

Videos

Panelists discuss how early clinical suspicion, genetic testing, cardiac biomarkers, and imaging techniques are crucial for diagnosing transthyretin amyloid cardiomyopathy (ATTR-CM), while also highlighting challenges such as common misdiagnoses and delayed diagnoses, which can significantly impact patient outcomes and quality of life.

Clinical Manifestation of ATTR-CM and Red Flag Symptoms

Summary for Physicians: Clinical Manifestations and Red Flag Symptoms of ATTR-CM

Heart failure (HF), often with restrictive cardiomyopathy

Atrial arrhythmias that are resistant to ablation procedures

 May cause discomfort or neurological deficits

 Common in patients with hereditary transthyretin amyloid cardiomyopathy (hATTR-CM)

May show signs of low-voltage QRS complexes, heart block, or other arrhythmias typical of restrictive cardiomyopathy

Echocardiography and cardiac MRI often show characteristic features of restrictive cardiomyopathy or amyloid deposits.

Elevated biomarkers such as NT-proBNP and troponins can be seen in cardiac involvement.

Genetic testing can confirm the diagnosis of hATTR-CM.

 should raise suspicion of hATTR-CM, especially in patients with unexplained HF or arrhythmias.

 or genetic mutations associated with ATTR-CM further supports the diagnosis.

Early recognition of these symptoms is essential for timely diagnosis and intervention in patients with ATTR-CM.

Panelists discuss how recognizing key clinical manifestations and red flag symptoms, such as bilateral carpal tunnel syndrome, spinal stenosis, and trigger fingers, is critical for early diagnosis and intervention in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), particularly in those with unexplained heart failure or arrhythmias.

Common TTR Gene Mutations

 (ATTR) disease is driven by mutations in the 

 gene, which encodes the TRR protein. In the United States, the most common mutations linked to 

 amyloidosis include several specific mutations in the TTR gene. These mutations are associated with a range of disease severities, primarily affecting cardiac and neurological systems. Below are the most common 

 mutation is the most common and most well-known mutation in hATTR amyloidosis, particularly in patients with 

peripheral neuropathy. It is most prevalent in Scandinavian countries but is also seen in the United States.

: This mutation is associated with a more aggressive form of the disease and can result in early-onset ATTR amyloidosis, typically presenting in patients in their 30s to 40s. Patients often experience both 

 symptoms, with neuropathy being one of the most debilitating features.

 mutation is found in a significant number of patients with hATTR amyloidosis, particularly in the African American population. This mutation is more commonly associated with 

 and may present with heart failure symptoms, often without significant peripheral neuropathy.

: It typically manifests in midlife or later and is characterized by 

, which may be misdiagnosed as other forms of heart failure, such as heart failure with preserved ejection fraction (HFpEF).

 mutation is another prevalent mutation in the United States, particularly among African American populations. It is considered one of the most common mutations associated with 

 has been linked to a form of ATTR amyloidosis that is more likely to present as 

, especially in older individuals. This form is often misdiagnosed as HFpEF, and symptoms may emerge after the age of 60.

 mutation is less common but still occurs in a subset of hATTR cases. It is associated with a more progressive form of the disease and tends to cause more severe neuropathy along with cardiomyopathy.

: This mutation typically presents in adulthood and causes both 

 manifestations, similar to the V30M mutation but with more variable progression.

Although the mutations mentioned above are the most common, numerous other rare mutations in the TTR gene can also cause ATTR amyloidosis. These include mutations such as 

, which may result in either cardiac or mixed cardiac-neurological forms of the disease.

 gene mutations in the United States include 

, each of which can lead to different clinical manifestations of hATTR amyloidosis. 

 is known for its early-onset, aggressive disease, whereas 

 is frequently seen in older African American individuals and is associated with cardiac symptoms. Identifying the specific 

 mutation is critical for accurate diagnosis, prognostication, and tailoring of treatment strategies, particularly as new therapies for hATTR amyloidosis become available. Genetic testing plays a key role in the diagnosis and management of these patients.

Panelists discuss how identifying the most common TTR gene mutations, including V30M, T60A, and V122I, is essential for accurate diagnosis, understanding clinical presentations, and tailoring treatment strategies for hereditary transthyretin amyloidosis in the United States.

The Pathophysiology of ATTR-CM, Differentiating Between wtATTR-CM and hATTR-CM

Summary for Physicians: Pathophysiology of ATTR-CM and the Importance of Differentiating Between wtATTR-CM and hATTR-CM

 (ATTR-CM) is a form of systemic amyloidosis where misfolded transthyretin (TTR) proteins accumulate as amyloid deposits in various organs, primarily in the heart. TTR is a protein responsible for transporting thyroid hormones and retinol-binding proteins, and it is produced mainly in the liver. When TTR undergoes misfolding due to mutations (in hereditary forms) or aging (in wild-type forms), it forms amyloid fibrils that deposit in tissues, leading to organ dysfunction, particularly in the heart.

, the amyloid fibrils accumulate in the myocardium, causing 

. Over time, this amyloid deposition can lead to stiffening of the heart muscle, impairing its ability to contract and relax, which results in reduced cardiac output and symptoms such as shortness of breath, fatigue, and arrhythmias.

Differentiating Between Wild-Type ATTR-CM (wtATTR-CM) and Hereditary ATTR-CM (hATTR-CM)

This form of ATTR-CM occurs due to the accumulation of normal (wild-type) TTR proteins that misfold and form amyloid deposits as people age. It primarily affects older individuals, especially men, and is commonly associated with heart failure with preserved ejection fraction. wtATTR-CM is often seen in patients older than 60 years and may be more prevalent than previously recognized, but it tends to progress more slowly and is often diagnosed later in the disease course.

hATTR-CM results from mutations in the TTR gene, which causes the production of abnormal TTR proteins that are prone to misfolding and amyloid deposition. The mutations may cause a more aggressive form of the disease that can present earlier in life, often in patients aged 30 to 50 years. hATTR-CM is inherited in an autosomal dominant manner, so there may be a family history of the disease. Certain mutations, such as the V30M mutation, are associated with more severe clinical outcomes, including earlier cardiac involvement, neuropathy, and multiorgan dysfunction.

Importance of Differentiating Between wtATTR-CM and hATTR-CM

: Treatment for wtATTR-CM focuses on symptom management, particularly heart failure treatment, as there are fewer disease-modifying therapies currently available for this form. However, emerging treatments, such as tafamidis, are starting to show promise in slowing disease progression.

: For hATTR-CM, specific disease-modifying treatments are available, such as 

 strategies. These therapies target the misfolded TTR protein directly and can prevent further amyloid deposition, improve cardiac function, and potentially halt disease progression. Early diagnosis and genetic testing are crucial for the timely initiation of these treatments.

 mutation is important not only for treatment but also for 

. Family members may be at risk, and early screening can help identify asymptomatic carriers who may benefit from early treatment.

 tends to have a slower progression, and the patient’s prognosis may be better compared to 

, which can progress rapidly and result in multiorgan damage. Understanding whether the patient has wtATTR-CM or hATTR-CM helps predict disease course and guide clinical decision-making.

 is critical for ensuring the correct diagnosis, appropriate treatment selection, and better management of patient outcomes. Although both forms share similar pathophysiology with TTR amyloid deposits in the heart, the underlying causes, progression, and treatment strategies differ significantly. Early diagnosis of hATTR-CM is particularly important for initiating disease-modifying therapies and providing genetic counseling to at-risk family members.

Panelists discuss how differentiating between wild-type transthyretin amyloid cardiomyopathy (wATTR-CM) and hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is essential for accurate diagnosis, tailored treatment strategies, and better management of patient outcomes, given their distinct pathophysiologies, disease progression, and treatment options.

Sharmila Dorbala, MD, MPH, MASNC

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