Amyloidosis is a disorder characterized by the extracellular accumulation of misfolded proteins as insoluble fibrils, which cause tissue damage and organ dysfunction. The different forms of amyloidosis are classified according to the amyloidogenic precursor, which influences the patterns of organ deposition, natural history and the therapeutic approach 1 . Currently, 36 forms of amyloidosis are recognized, classified according to the type of protein accumulating in tissues 1 . Amyloid transthyretin (ATTR) amyloidosis is one of the most common forms of amyloidosis 2 , caused by tissue deposition of full-length and fragmented monomers of transthyretin (TTR).TTR is a homotetrameric protein that, in humans, is synthesized mainly in the liver and choroid plexus, from which it is secreted into the plasma and the cerebrospinal fluid, respectively 2 . In the plasma, TTR can bind to and transport the thyroid hormone thyroxine (T4), accounting for approximately 15% of the bound T4 pool; other carriers of T4 in the plasma include thyroxine-binding globulin (the major carrier) and albumin 2 . By contrast, in the cerebrospinal fluid, TTR is the major T4 carrier, transporting 80% of the hormone 2 . In addition, TTR also mediates the transport of vitamin A by associating with retinol-binding protein 4 (RBP4), which is the main carrier of vitamin A 2 . In agarose gel electrophoresis, TTR migrates in front of the albumin band, which is why TTR was formerly known as pre-albumin. Normal plasma concentrations of TTR vary between 20 mg/dl and 40 mg/dl (ref. 3 ).The TTR gene is located on chromosome 18q12.1 and encodes a 55-kDa tetramer with four identical monomers of 127 amino acids, each forming a β-sandwich with one small α-helix and eight β-strands 3 . During the 1990s, Kelly et al. demonstrated that dissociation of tetrameric TTR into monomers was followed by a rapid misfolding and misassembling of the monomers into aggregates, at least in vitro and in non-physiological conditions (low pH) 4,5 . A highly specific cleavage of the amyloid precursor by serine proteases might be particularly important to prime TTR fibrillogenesis under physiological conditions 6 . Among the >130 TTR variants identified 7 , the vast majority are pathogenic and favour tetramer dissociation 8 , whereas a few benign

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Aims The HFA‐PEFF and H2FPEF scores have been developed to diagnose heart failure with preserved ejection fraction (HFpEF), and hold prognostic value. Their value in patients with HFpEF caused by cardiac amyloidosis (CA) has never been investigated. Methods and results We evaluated the diagnostic and prognostic value of the HFA‐PEFF and H2FPEF scores in 304 patients from three cohorts with HFpEF caused by transthyretin CA (n = 160, 53%) or immunoglobulin light‐chain CA (n = 144, 47%). A diagnosis of HFpEF was more likely using the HFA‐PEFF score with 2 (1%), 71 (23%), and 231 (76%) patients ranked as having a low (0–1), intermediate (2–4), or high (5, 6) probability of HFpEF, respectively. Conversely, 36 (12%), 179 (59%) and 89 (29%) of patients ranked as having a low (0–1), intermediate (2–5), or high (6–9) probability of HFpEF using the H2FPEF score. During a median follow‐up of 19 months (interquartile range 8–40), 132 (43%) patients died. The HFA‐PEFF score, but not the H2FPEF score, predicted a high risk of all‐cause death which remained significant after adjustment for age, AL‐CA diagnosis, high‐sensitivity troponin T, N‐terminal pro‐B‐type natriuretic peptide, and echocardiographic parameters, including left ventricular global longitudinal strain, left ventricular diastolic function and right ventricular function (hazard ratio 1.51, 95% confidence interval 1.16–1.95, p = 0.002 for every 1‐point increase in HFA‐PEFF). Conclusions The HFA‐PEFF score has a higher diagnostic utility in HFpEF caused by CA and holds independent prognostic value for all‐cause mortality, while the H2FPEF score does not.

Aims Cardiac amyloidosis (CA) affects the four heart chambers, which can all be evaluated through speckle-tracking echocardiography (STE). Methods and results We evaluated 423 consecutive patients screened for CA over 5 years at two referral centres. CA was diagnosed in 261 patients (62%) with either amyloid transthyretin (ATTR; n = 144, 34%) or amyloid light-chain (AL; n = 117, 28%) CA. Strain parameters of all chambers were altered in CA patients, particularly those with ATTR-CA. Nonetheless, only peak left atrial longitudinal strain (LA-PALS) displayed an independent association with the diagnosis of CA or ATTR-CA beyond standard echocardiographic variables and cardiac biomarkers (Model 1), or with the diagnosis of ATTR-CA beyond the validated IWT score in patients with unexplained left ventricular (LV) hypertrophy. Patients with the most severe impairment of LA strain were those most likely to have CA or ATTR-CA. Specifically, LA-PALS and/or LA-peak atrial contraction strain (PACS) in the first quartile (i.e. LA-PALS <6.65% and/or LA-PACS <3.62%) had a 3.60-fold higher risk of CA, and a 3.68-fold higher risk of ATTR-CA beyond Model 1. Among patients with unexplained LV hypertrophy, those with LA-PALS or LA-PACS in the first quartile had an 8.76-fold higher risk for CA beyond Model 1, and a 2.04-fold higher risk of ATTR-CA beyond the IWT score. Conclusions Among STE measures of the four chambers, PALS and PACS are the most informative ones to diagnose CA and ATTR-CA. Patients screened for CA and having LA-PALS and/or LA-PACS in the first quartile have a high likelihood of CA and ATTR-CA.

Aims The HFA-PEFF and H2FPEF scores have been developed to diagnose heart failure with preserved ejection fraction (HFpEF), and hold prognostic value. Their use in patients with HFpEF caused by cardiac amyloidosis (CA) has never been investigated. Methods and results We evaluated the diagnostic and prognostic value of the HFA-PEFF and H2FPEF scores in 304 patients from 3 cohorts with HFpEF caused by transthyretin (ATTR)-CA (n=160, 53%) or immunoglobulin light-chain (AL)-CA (n=144, 47%). A diagnosis of HFpEF was more likely using the HFA-PEFF score with 2 (1%), 71 (23%), and 231 (76%) patients ranked as having a low (0–1), intermediate (2–4) or high (5–6) probability of HFpEF, respectively. Conversely, 36 (12%), 179 (59%) and 89 (29%) of patients ranked as having a low (0–1), intermediate (2–5) or high (6–9) probability of HFpEF using the H2FPEF score. During a median follow-up of 19 months (interquartile range 8–40), 132 (43%) patients died. The HFA-PEFF score, but not the H2FPEF, predicted a high risk of all-cause death which remained significant after adjustment for age, AL-CA diagnosis, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and echocardiographic parameters, including left ventricular (LV) global longitudinal strain, LV diastolic function and right ventricular function (hazard ratio 1.51, 95% confidence interval 1.16–1.95, p=0.002 for every 1-point increase in HFA-PEFF). Conclusions The HFA-PEFF score has a high sensitivity to diagnose HFpEF caused by CA and holds independent prognostic value for all-cause mortality, while the H2FPEF score does not. Funding Acknowledgement Type of funding sources: None.