What is Amyloid Transthyretin (ATTR) Cardiomyopathy (CM)?

From the Guidelines

ATTR-CM is a progressive heart disease caused by the buildup of abnormal protein deposits (amyloid) in the heart muscle, specifically characterized by the misfolding of transthyretin (TTR) protein, leading to restrictive cardiomyopathy (CM) 1. The condition occurs when TTR, a protein produced by the liver, becomes unstable and forms amyloid fibrils that accumulate in the heart walls, making them stiff and thick 1. This leads to heart failure symptoms like shortness of breath, fatigue, and fluid retention.

Key Characteristics of ATTR-CM

• Two forms: hereditary (caused by genetic mutations, formerly referred to as “familial” ATTR-CM) and wild-type (age-related, typically affecting older men, formerly referred to as “senile” or “age-related” ATTR-CM) 1
• TTR misfolding and aggregation appear to increase with aging, with autopsy series indicating that 25% of patients over 80 years of age harbor TTR amyloid deposits 1
• Over 130 known TTR variants associated with ATTR amyloidosis, with the most common in the United States being the substitution of isoleucine for valine at position 122 of the protein sequence (reported as pV142I or Val122Ile or V122I) 1

Diagnosis and Treatment

• Clinical recognition and diagnosis of cardiac amyloidosis at an early stage of the disease is critical, affording an affected patient the widest array of treatment options that have a favorable impact on survival and/or prevent potentially irreversible loss of physical function and quality of life 1
• Imaging techniques and monoclonal light chain testing now allow for accurate noninvasive diagnosis of ATTR-CM in the proper clinical context without the need for confirmatory endomyocardial biopsies 1
• Treatment options include medications that stabilize transthyretin proteins to prevent misfolding, as well as heart failure medications to manage symptoms 1

Importance of Early Diagnosis

• Early diagnosis is crucial as treatments work best before significant heart damage occurs 1
• Without treatment, ATTR-CM progressively worsens, leading to severe heart failure and reduced life expectancy 1

From the FDA Drug Label

VYNDAQEL and VYNDAMAX are indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

Amyloid Transthyretin (ATTR) Cardiomyopathy (CM) is a condition where the heart muscle becomes stiff due to the accumulation of abnormal amyloid proteins, specifically transthyretin. This can lead to reduced heart function and increased risk of cardiovascular mortality and hospitalization. The drug labels for tafamidis (2, 2, 2) indicate that it is used to treat this condition in adults.

• Key characteristics:
  • Involves accumulation of abnormal amyloid proteins (transthyretin) in the heart muscle
  • Leads to stiffening of the heart muscle
  • Increases risk of cardiovascular mortality and hospitalization
• Treatment: Tafamidis is indicated for the treatment of ATTR-CM in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

From the Research

Definition and Overview of Amyloid Transthyretin (ATTR) Cardiomyopathy (CM)

• Amyloid Transthyretin (ATTR) Cardiomyopathy (CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment 3.
• It is characterized by the aggregation and deposition of amyloidogenic misfolded transthyretin (TTR) in the myocardium, leading to restrictive cardiomyopathy and heart failure 4.
• ATTR-CM can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms) 3.

Clinical Manifestations and Diagnosis

• ATTR-CM is an underrecognized cause of heart failure (HF) and can lead to a number of cardiovascular manifestations, including HF, rhythm disturbances, and valvular disease 5.
• Early clinical recognition and prompt diagnosis are crucial to improving disease-related outcomes, and advances in diagnostic modalities and therapeutic options have increased the prevalence of ATTR-CM 5.
• Monitoring disease progression is challenging and currently lacks best-practice guidance, but experts recommend a multiparametric evaluation, including clinical and functional endpoints, biomarkers and laboratory markers, and imaging and electrocardiographic parameters 6.

Treatment Options

• Tafamidis, a TTR stabilizer, has been approved for use in the treatment of adults with ATTR-CM in several countries and has been shown to reduce all-cause mortality and frequency of cardiovascular-related hospitalizations 4.
• Other treatment options, including green tea, tolcapone, and diflunisal, are used off-label in ATTR-CM patients, and novel therapies using RNA interference, such as patisiran and inotersen, are under investigation 7.
• Monoclonal antibodies in the early development phases carry hope for amyloid deposit clearance, but the small ATTR-CM patient population raises several challenges for clinical development 7.