Aim of the study

Although transthyretin amyloid cardiomyopathy (ATTR-CM) is a recognized contributor to heart failure in older adults, it remains frequently misdiagnosed or identified late in the disease course. The TTRACK study aimed to determine the prevalence and characteristics of ATTR-CM in older patients with hypertrophic cardiomyopathy (HCM), as defined by the 2014 European Society of Cardiology (ESC) guidelines, and without an already identified aetiology.

Methods

• Multicentre, non-interventional, cross-sectional, epidemiological study conducted at 20 centres across 11 countries.
• Inclusion criteria: Patients aged ≥50 years with HCM, defined by the 2014 ESC guidelines (maximal end-diastolic left ventricular wall thickness ≥15 mm on echocardiography), and no identified genetic or alternative origin.
• Eligible patients underwent 99mTechnetium (99mTc) bone scintigraphy.
• Patients with grades 1–3 cardiac uptake underwent standard clinical evaluation, monoclonal protein testing, and transthyretin (TTR) gene sequencing.
• Patients with grade 2 or 3 cardiac uptake and no monoclonal protein abnormalities were classified as having ATTR-CM, according to established guidelines for non-biopsy diagnosis of cardiac amyloidosis (CA), either as variant or wild-type.

Results 

• A total of 766 patients were included in the study. The mean age was 72.3 ± 10.6 years, and 69.6% were men.
• 691 patients (90.2%) underwent scintigraphy alone, while 75 patients (9.8%) had scintigraphy plus SPECT.
• 144 patients (18.8%) had grade 2 or 3 cardiac uptake with no evidence of plasma cell dyscrasia and were diagnosed with ATTR-CM.
  • Among these, 11 patients (7.6%) had variant ATTR-CM, and 123 patients (85.4%) had wild-type ATTR-CM.
• The mean age was:
  • 68.3 ± 9.3 years for variant ATTR-CM
  • 78.6 ± 8.8 years for wild-type ATTR-CM.
• The majority were men (82% for variant ATTR-CM and 85% for wild-type ATTR-CM).
• The most common TTR gene variants were:
  • V142I (n = 4)
  • I88L (n = 2)
  • V50M (n = 2).
• Approximately 19% of the study population had ATTR-CM. Among those diagnosed, ~8% had variant ATTR-CM.

Main messages 

HCM is a myocardial disorder characterized by increased left ventricular wall thickness unexplained by abnormal loading conditions. While HCM is often a heritable condition caused by variants in genes encoding cardiac sarcomere proteins, other conditions such as nongenetic HCM and rare genetic diseases, including CA, can mimic its presentation. 
The global incidence and prevalence of CA are increasing, largely due to advancements in diagnostic pathways, including the widespread use of imaging techniques and greater availability of genetic testing. However, many cases continue to be misdiagnosed or identified late in the disease course, which is particularly concerning as disease-modifying therapies are now available. Early recognition is therefore essential to improving outcomes.
In this study, the authors investigated an older population, aged ≥ 50 years, to identify the prevalence and characteristics of ATTR-CM in patients with unexplained left ventricular hypertrophy. Patients with severe aortic stenosis, pathogenic sarcomere gene variants, or other disease phenocopies were excluded. The study aimed to recruit approximately 1500 patients, based on the estimated prevalence of ATTR-CM; however, the final sample size was limited to 766 patients due to recruitment challenges related to the COVID-19 pandemic. This limitation, combined with the absence of details regarding preliminary screening, diagnostic workup, and genetic testing, introduces the possibility of selection bias.

The study included 766 patients recruited across 20 medical centres in 11 countries. Of these, 144 patients (18.8%) were diagnosed with ATTR-CM, having grade 2 or 3 bone scintigraphy uptake and no evidence of plasma cell dyscrasia. Genetic testing revealed that 11 patients (7.6%) had variant ATTR-CM, while 123 patients (85.4%) had wild-type ATTR-CM. 
Notably, only about 10% of patients underwent bone scintigraphy combined with single-photon emission computed tomography (SPECT), as is now recommended. There was considerable variability in results depending on the radiotracer used. The prevalence of ATTR-CM was 11.7% with 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), 6.4% with 99mTc-pyrophosphate (PYP), and 26.9% with 99mTc-hydroxymethylene diphosphonate (HMDP). Although, the comparative performance of the different tracers remains uncertain, caution is needed when interpreting these results. Further studies are needed to clarify their diagnostic accuracy and standardize their use. 
Classical echocardiographic signs described in HCM, such as asymmetric hypertrophy and LV outflow tract obstruction, were observed in patients with ATTR-CM in the   cohort (in 20% and 13%, respectively), underscoring the need for clinicians to consider ATTR-CM in patients ≥50 years of age with HCM, irrespective of atypical echocardiography finding
One of the purposes of the study was to identify other signs and symptoms associated with ATTR-CM. On multivariate analysis, carpal tunnel syndrome (odds ratio [OR] 54.3; P < 0.0001) and male sex (OR 7.9; P < 0.0001) were the strongest predictors of ATTR-CM. Additionally, left ventricular septal wall thickness (OR 1.8; 95% CI 1.1–2.9) and age (cR 1.9; 95% CI 1.6–2.2) were also found to be independent predictors.
Interestingly, N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT-HS), which are widely used biomarkers for cardiac amyloidosis, were not significantly associated with ATTR-CM on univariable regression analysis in this population with left ventricular hypertrophy. Importantly, nearly one-quarter of the patients diagnosed with ATTR-CM in this study were in New York Heart Association (NYHA) functional class I, highlighting that ATTR-CM can present even in the absence of heart failure symptoms and emphasizing the need for a high index of suspicion for the disease.
This study’s non-interventional design meant that endomyocardial biopsy was not performed. As a result, some cases with grade 1 bone scintigraphy uptake may have been missed, and further subtyping could not be validated in patients with grade 2 or 3 uptake and monoclonal abnormalities. 
Nevertheless, the study found that approximately 19% of older patients with unexplained HCM had ATTR-CM, highlighting its significant prevalence in this population. Despite its limitations, the findings underscore the importance of considering ATTR-CM as a differential diagnosis in older patients with left ventricular hypertrophy.