Prognosis of Transthyretin Cardiac Amyloidosis Without Heart Failure Symptoms

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers. Objectives The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. Methods Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. Results A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002). Conclusions After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.

T ransthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal cardiomyopathy caused by the extracellular deposition of transthyretin (TTR) amyloid fibrils in the heart, either in its variant or wild-type form. 1 Advances in noninvasive imaging techniques as well in the definition of noninvasive diagnostic criteria and the availability of new treatments have led to increased recognition of ATTR-CM, and patients are now diagnosed at earlier disease stages. [2][3][4][5][6] Several studies have demonstrated the important contribution of ATTR-CM to heart failure (HF) in elderly patients. [7][8][9] Once HF is present, ATTR-CM is associated with a life expectancy of only 2.5 to 3.5 years if left untreated, but no data are available on the prognosis and natural history of patients with ATTR-CM diagnosed at earlier stages. [10][11][12] As a result, delineating prognosis in this growing group of patients is problematic.
Tafamidis, a TTR stabilizer that attenuates TTR dissociation and thereby slows amyloid fibril formation, was recently shown to reduce mortality and cardiac hospitalizations in patients with symptomatic HF with ATTR-CM. 13 Additional studies evaluating other stabilizers or TTR gene-silencing agents are ongoing, but again these studies include only patients with ATTR-CM and clinical HF. 14 As a consequence, it is unknown whether patients with ATTR-CM without HF symptoms could benefit from early initiation of specific therapies.
Here, we sought to characterize patients with ATTR-CM without HF symptoms and to describe their outcomes and prognosis. We also explored the effects of disease-modifying therapies in the subgroup of patients already taking these drugs despite the absence of HF symptoms.

METHODS
The present study conforms to the principles of the Declaration of Helsinki, and all authors guarantee the integrity of data from their respective institutions.
Approval from a local ethics committee or internal review board was obtained at each participating center. COHORT    Values are n (%), median (IQR), or mean AE SD. a At baseline or started during the first 6 months after initial evaluation.
NYHA functional class at last follow-up (n ¼ 114) Values are median (IQR), n, or mean AE SD.
AV ¼ atrioventricular; CV ¼ cardiovascular; HF ¼ heart failure; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; other abbreviations as in Table 1.     Clinical, echocardiographic and electrocardiographic findings at baseline and at last follow-up of patients treated or not with stabilizers are shown in Table 3. Two patients who received TTR stabilizers and also underwent liver transplantation were excluded from the analysis. Similarly, 3 patients who did not receive stabilizers and received gene silencers  Table 3).

DISCUSSION
This multicenter study presents, for the first time to our knowledge, data on patients with ATTR-CM without HF symptoms at diagnosis. We show that one-third of these patients developed HF during a median follow-up period of 3.7 years and that a  The median overall survival described for stage I Abbreviations as in Tables 1 and 2. and ultimately death, which is usually CV in nature and due to underlying disease. 5,6,19 Access to novel, effective, and specific compounds for both ATTR-wt and ATTR-v has recently grown and has the potential to change the natural course of the disease. Therapies that reduce the production of  Analysis of a cohort of 118 patients with transthyretin amyloid cardiomyopathy recruited from 6 international amyloid centers showed that after a median follow-up period of 3.7 years, 32% patients developed heart failure (HF) symptoms, with a cumulative incidence of HF onset at 1, 3, and 5 years of 8% (95% CI: 4%-14%), 15% (95% CI: 9%-23%), and 27% (95% CI: 18%-37%), respectively. Treatment with transthyretin stabilizers was associated with improved survival.