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

1. Pathophysiology of ATTR-CM:

• Transthyretin amyloid cardiomyopathy (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.
• In ATTR-CM, the amyloid fibrils accumulate in the myocardium, causing diastolic dysfunction, restrictive cardiomyopathy, and heart failure. 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.

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

• wtATTR-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:
  • 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.

1. Importance of Differentiating Between wtATTR-CM and hATTR-CM:

• Treatment implications:
  • wtATTR-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.
  • hATTR-CM: For hATTR-CM, specific disease-modifying treatments are available, such as TTR stabilizers (eg, tafamidis), RNA interference therapies (eg, patisiran, inotersen), and gene silencing 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.
• Genetic counseling:
  • In hATTR-CM, identifying the specific TTR mutation is important not only for treatment but also for genetic counseling. Family members may be at risk, and early screening can help identify asymptomatic carriers who may benefit from early treatment.
• Prognostic differences:
  • wtATTR-CM tends to have a slower progression, and the patient’s prognosis may be better compared to hATTR-CM, 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.

Conclusion:
Differentiating between wtATTR-CM and hATTR-CM 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.