Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, in ﬁ ltrative disease caused by the deposition of transthyretin amyloid ﬁ brils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here we propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic “ red ﬂ ags ” that can assist in its diagnosis among the wider population of patients with heart failure. (J Am Coll Cardiol HF 2019; - : - – - ) © 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This

T ransthyretin amyloid cardiomyopathy (ATTR-CM) represents 1 of the 2 most common types of cardiac amyloidosis, an infiltrative heart muscle disease caused by extracellular deposition of misfolded proteins which form insoluble amyloid fibrils (1,2). ATTR-CM is a lifethreatening, progressive disease that can affect the heart in isolation or as part of a systemic disorder (2)(3)(4). The other main type of cardiac amyloidosis is light-chain (AL) amyloidosis, which arises from overproduction and misfolding of monoclonal immunoglobulin light chains (2). AL amyloidosis is a relatively rare disease, characterized by a rapidly progressive clinical course which, if untreated, has a median survival of less than 6 months (5).
ATTR-CM is caused by deposition of transthyretin (TTR), a plasma protein predominantly produced in the liver, which is responsible for transporting thyroxine and retinol (1,6). TTR mainly exists in a tetrameric state, but destabilizing mutations in the transthyretin gene (TTR) and/or aging promote its proteolytic remodeling and dissociation into monomers which subsequently misfold and aggregate to form amyloid fibrils that deposit in tissues (1,2,4,6).
In the case of ATTR-CM, amyloid fibrils mainly deposit in the interstitial space of the myocardium leading to increased wall thickness and diastolic dysfunction that can result in heart failure (HF) and arrhythmias (2). ATTR-CM exists as 1 of 2 subtypes, defined by the precursor TTR protein. Hereditary, or mutant, ATTR (ATTRm) amyloidosis is caused by the presence of TTR mutations, resulting in a less stable TTR protein (1). Wild-type ATTR (ATTRwt) amyloidosis, previously referred to as "senile systemic amyloidosis," is a result of age-related changes in wild-type TTR stability (1,4,7).
EPIDEMIOLOGY OF ATTRm. The prevalence of ATTRm is difficult to establish due to the variable geographical distribution of TTR mutations. Some mutations are endemic in certain regions, but recent estimates suggest that the prevalence in Europe is less than 1 in 100,000 (8). Conversely, although endemic in some areas of Japan, the overall prevalence in Japan is thought to be much lower, approximately 1 in 1,000,000 (9). The valine 122 isoleucine substitution TTR mutation most commonly affects individuals of Sub-Saharan African ancestry and has an allele prevalence of 3% to 4% within the African-American population (10).
EPIDEMIOLOGY OF ATTRwt. Recent data suggest that ATTR-CM is overlooked as a cause of common cardiovascular conditions in older people, with relatively high rates among individuals diagnosed with HF with preserved ejection fraction (HFpEF) (11), lowflow aortic stenosis, and settings of increased wall thickness (3). Additionally, autopsy data have shown that among adults 80 years of age or older, 25% have significant TTR amyloid deposits in the myocardium (12). Despite being historically considered a disease of older age, there have been reports of diagnosis of ATTRwt in patients as young as 47 years (13).
Although the exact prevalence of ATTRwt is unknown, it is almost certainly the most common cause of cardiac amyloidosis, particularly in the elderly, potentially accounting for up to 10% of elderly patients with HF (1,4). With a convenient and relatively inexpensive imaging modality, bone scintigraphy, having strong evidence as an accurate, noninvasive approach to diagnosing ATTR-CM (14,15), the number of patients identified as having this condition will undoubtedly increase in the future.

ATTR-CM MANIFESTATIONS AND MANAGEMENT
Although ATTR-CM commonly presents with symptoms of HF or arrhythmias, amyloidosis is a systemic disease and can cause various noncardiac symptoms (3,16). Ophthalmological, neurological, and gastrointestinal symptoms can all be extracardiac signs of cardiac amyloidosis, particularly in ATTRm (1,16).
Medical management of ATTR-CM remains a significant unmet need, with treatments for ATTR-CM currently being limited to the alleviation of HF symptoms, including sodium restriction or aldosterone antagonists in combination with loop diuretics (2,4). Heart transplantation alone or, in some ATTRm patients, in combination with liver transplantation, is an option for selected patients, but there are major  Screening Recommendations for ATTR-CM -2 0  When developing a screening tool to aid in the recognition of a disease, one should consider the disease prevalence; the ease, impact, and accuracy of diagnostic testing; and the potential for effective treatment. In the case of ATTR-CM, prevalence is likely higher than initially thought (15), bone scintigraphy represents a low-cost, low-impact diagnostic test (14), and there is now a drug approved by the FDA and in other countries with proven efficacy and safety in a phase III clinical trial (18,19), with others in development (1). Therefore, a broad screening approach to identify ATTR-CM is recommended within certain clinical scenarios (Central Illustration).

CLINICAL SCENARIOS THAT WOULD WARRANT SCREENING FOR ATTR-CM
The most common symptom of ATTR-CM is HF (1). in men older than 65 years or women older than 70 years are expected to represent a significant rate of diagnosis, supporting the investigation of disease etiology through screening of these patients.

RED FLAGS FOR ATTR-CM
Clinical clues or red flags that should further heighten suspicion or alert clinicians to the possibility of