Key Information
Awareness of transthyretin amyloid cardiomyopathy (ATTR-CM) has increased over the years due to diagnostic and therapeutic developments. Timely initiation of novel disease-modifying treatments improves both morbidity and mortality, which underlines the necessity for a prompt diagnosis. Nevertheless, early diagnosis of ATTR-CM remains challenging. This is a retrospective observational cohort study of patients diagnosed with ATTR-CM. Between 2016 and 2023, 87 patients were diagnosed with cardiac amyloidosis of which 65 (75%) patients with ATTR-CM and 22 (25%) patients with light chain amyloidosis. This study included 65 ATTR-CM patients (mean age 77 ± 7 years; 86% male) of whom 59 (91%) with wild-type ATTR-CM (ATTRwt) and six (9%) with variant ATTR-CM. We observed a surge in ATTR-CM diagnoses from 3 patients/year (2016–2020) to 16 patients/year (2021–2023), driven by ATTRwt. Nevertheless, the interval between the onset of heart failure symptoms and ATTR-CM diagnosis has not changed significantly (2016–2020 27.3 months [18.6–62.4]; 2021–2023 30.0 months [8.6–57.2]; p = 0.546), driven by time to referral. Red flags for ATTR-CM preceded diagnosis by several years: left ventricular hypertrophy (79%, 5.8 years [3.3–7.0]) and carpal tunnel syndrome (49%, 6.8 years [2.3–12.1]). Despite the presence of typical red flags, symptom-to-diagnosis duration has remained similar driven by time to referral. Improved recognition of red flags for ATTR-CM could reduce the time to diagnosis and improve overall recognition.
Introduction
Amyloidosis is a spectrum of diseases in which misfolded proteins aggregate into amyloid fibrils, causing extracellular depositions in various tissues and organs. Cardiac amyloidosis (CA) is characterized by depositions of these insoluble amyloid fibrils in the interstitial space between cardiac myocytes, leading to left ventricular hypertrophy (LVH), heart failure and conduction disorders. Amyloid formation can be caused by various proteins, but two precursor proteins alone cause up to 98% of CA cases [1external link, opens in a new tab]. One of these proteins is transthyretin (TTR), a serum transporter protein synthesised by the liver. Rarely, TTR amyloid fibrils are formed due to a mutation in the TTR gene (variant); more commonly, it is due to unresolved reasons related to ageing (wild-type). Second, in cardiac light chain amyloidosis (AL-CA), amyloid fibrils are created from abnormal light chains generated by monoclonal plasma cells [1external link, opens in a new tab].
Transthyretin amyloid cardiomyopathy (ATTR-CM) was long thought to be a rare disease. However, awareness of ATTR-CM has improved as a result of non-invasive diagnostic and disease-modifying therapeutic developments, and recent studies have suggested that it is more common than previously anticipated. The prevalence of ATTR-CM has been reported to vary between 6 and 25% in diverse population cohorts [2external link, opens in a new tab,3external link, opens in a new tab,4external link, opens in a new tab,5external link, opens in a new tab,6external link, opens in a new tab,7external link, opens in a new tab]. At this moment, ATTR-CM progression can only be mitigated rather than completely stopped or even reversed. Consequently, timely initiation of novel disease-modifying treatments is required at early stages of ATTR-CM to improve morbidity and mortality, which strikes the necessity for a prompt and early diagnosis [8external link, opens in a new tab,9external link, opens in a new tab,10external link, opens in a new tab]. Nevertheless, early diagnosis of ATTR-CM remains challenging and diagnosis is often delayed [11external link, opens in a new tab,12external link, opens in a new tab,13external link, opens in a new tab]. Delayed diagnosis of ATTR-CM can be attributed to several factors, including unawareness of the disease, heterogenic and non-specific symptoms at early stages, and overlapping conditions with subsequent misdiagnosis [14external link, opens in a new tab, 15external link, opens in a new tab].
ATTR-CM may occur as an isolated disease, but more commonly it is part of a multisystemic disorder with several extra-cardiac manifestations [1external link, opens in a new tab]. Recognition of early cardiac and extra-cardiac manifestations may provide a more timely diagnosis and earlier therapy initiation. Nevertheless, it is uncertain as to whether increased awareness of cardiac and extra-cardiac manifestations of ATTR-CM has contributed to a reduction in the diagnostic delay of ATTR-CM over the years or if it has solely resulted in an augmentation of ATTR-CM diagnoses. Multiple studies have presented conflicting findings on this matter [3external link, opens in a new tab, 11external link, opens in a new tab, 16external link, opens in a new tab, 17external link, opens in a new tab]. Moreover, it is known that the translation of scientific advancements into practical application takes time, especially within smaller healthcare institutions [18external link, opens in a new tab]. Notably, the European Society of Cardiology (ESC) published its position paper in 2021 [1external link, opens in a new tab], potentially leading further to heightened awareness and possible reductions in diagnostic delay of ATTR-CM after 2021.
Acknowledging the importance of recognizing and overcoming diagnostic challenges for cardiac amyloidosis, this study evaluates the frequency and diagnostic trajectory of ATTR-CM in a tertiary medical centre in the Netherlands, with emphasis on improving time to diagnosis. Moreover, analyses were conducted to examine the clinical characteristics of patients and the presence of typical red flags associated with ATTR-CM, with a comparative assessment between patients diagnosed before and after publication of the ESC position paper and between the wild-type (ATTRwt) and variant (ATTRv) forms of ATTR-CM.