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. The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. 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). 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.

The introduction of a noninvasive diagnostic algorithm in 2016 led to increased awareness and recognition of cardiac amyloidosis (CA). The purpose of this study was to analyze the impact of the introduction of the noninvasive diagnostic algorithm on diagnosis and prognosis in a multicenter Italian CA cohort. This was a retrospective analysis of 887 CA patients from 5 Italian Cardiomyopathies Referral Centers: 311 light-chain CA, 87 variant transthyretin (TTR)-related CA, 489 wild-type TTR-related CA. Clinical characteristics and outcomes (all-cause mortality and heart failure [HF] hospitalizations) were compared overall and for each CA subtype between patients diagnosed before versus after 2016. Outcomes were further compared by propensity score weighted Kaplan-Meier analysis and Cox regression analysis. CA diagnoses increased after 2016, in particular for wild-type TTR-related CA. Patients diagnosed after versus before 2016 were older, had less frequently a history of HF prior to diagnosis, and NYHA functional class III-IV at diagnosis. Over a median follow-up of 18 months, 172 (86%) patients diagnosed before 2016 died or had an HF hospitalization, versus 300 (44%) diagnosed after 2016. Propensity score weighted Kaplan-Meier analysis showed worse outcomes (P < 0.001) for patients diagnosed before 2016. At Cox regression analysis, CA diagnosis after 2016 was an independent protective factor for the composite outcome (HR: 0.69; P = 0.001), with interaction by CA subtype (significant in TTR-related CA and null in light-chain). CA patients diagnosed after 2016 showed a less severe phenotype and a better prognosis. The impact of the noninvasive diagnostic algorithm on outcomes was particularly relevant in TTR-related CA.

Objective We sought to investigate prevalence, incidence and prognostic implications of permanent pacemaker (PPM) implantation in patients with cardiac amyloidosis (CA), thereby identifying the predictors of time to PPM implantation. Methods Seven hundred eighty-seven patients with CA (602 men, median age 74 years, 571 transthyretin amyloidosis (ATTR), 216 light-chain amyloidosis (AL)) evaluated at two European referral centres were retrospectively included. Clinical, laboratory and instrumental data were analysed. The associations between PPM implantation and mortality, heart failure (HF) or a composite endpoint of mortality, cardiac transplantation and HF were analysed. Results 81 (10.3%) patients had a PPM before initial evaluation. Over a median follow-up time of 21.7 months (IQR 9.6–45.2), 81 (10.3%) additional patients (18 with AL (22.2%) and 63 with ATTR (77.8%)) underwent PPM implantation with a median time to implantation of 15.6 months (IQR 4.2–40), complete atrioventricular block was the most common indication (49.4%). Independent predictors of PPM implantation were QRS duration (HR 1.03, 95% CI 1.02 to 1.03, p<0.001) and interventricular septum (IVS) thickness (HR 1.1, 95% CI 1.03 to 1.17, p=0.003). The model to estimate the probability of PPM at 12 months and containing both factors showed a C-statistic of 0.71 and a calibration of slope of 0.98. Conclusions Conduction system disease requiring PPM is a common complication in CA that affects up to 20.6% of patients. QRS duration and IVS thickness are independently associated with PPM implantation. A PPM implantation at 12 months model was devised and validated to identify patients with CA at higher risk of requiring a PPM and who require closer follow-up.

BACKGROUND: Thresholds to define prognosis with hs-cTnI (high-sensitivity cardiac troponin I) have not been systematically addressed in wild-type transthyretin amyloid cardiomyopathy, in part because of the multiplicity of hs-cTnI assays. The aims of this study were: first, to assess the prognostic performance of hs-cTnI measured with different assays in patients with wild-type transthyretin amyloid cardiomyopathy and, second, to identify assay-specific hs-cTnI thresholds for prognosis that could be integrated into staging systems for risk stratification. METHODS: Observational multicenter study of stable wild-type transthyretin amyloid cardiomyopathy patients from different cohorts using the Abbott Architect Stat hs-cTnI assay and the Beckman Coulter Access hs-cTnI assay (testing cohorts) and the Siemens Centaur XPT hs-cTnI assay (validation cohort). Outcome was all-cause mortality. RESULTS: In the Abbott cohort (n=136; median follow-up 22 [13–41] months; 31 [23%] deaths) and Beckman cohort (n=98; median follow-up 19 [12–28] months; 16 [16%] deaths), natural log-transformed hs-cTnI was an independent predictor of mortality (age- and sex-adjusted hazard ratio, 1.62 [95% CI, 1.11–2.35]; P =0.012 and 2.47 [95% CI, 1.48–4.14]; P 80 ng/L) and NPs (natriuretic peptides; NT-proBNP [N-terminal pro-B-type natriuretic peptide] >3000 ng/L or BNP [B-type natriuretic peptide] >250 ng/L) identified 3 groups with progressively worse prognosis. The staging system (using hs-cTnI >80 ng/L and NT-proBNP>3000 ng/L) was then applied to an independent cohort evaluated with the hs-cTnI Siemens assay (n=345, median follow-up 32 [24-42] months, 119 [34%] deaths). The significant differences between the groups were maintained. CONCLUSIONS: In patients with wild-type transthyretin amyloid cardiomyopathy, hs-cTnI is a strong and independent predictor of mortality. A threshold of hs-cTnI of 80 ng/L for these 3 assays provides effective risk stratification alone and in a staging system with NP.

Background: Despite major advances, the recognition of arrhythmogenic left ventricular cardiomyopathy (ALVC) remains challenging, since this clinical entity is often concealed in different clinical settings both in terms of clinical onset and imaging phenotype, resulting in significant delays in diagnosis with prognostic implications. Purpose: To describe a single Center cohort of ALVC patients, focusing on the spectrum of clinical presentation and diagnostic pathways. Methods: Patients were retrospectively evaluated between January 2012 and January 2022. Diagnosis was based on 1) ≥3 contiguous segments with subepicardial/midwall LGE in the LV at cardiac magnetic resonance (CMR) plus a likely pathogenic/pathogenic arrhythmogenic cardiomyopathy (ACM) associated genetic mutation and/or familial history of ACM and/or red flags for ALVC (i.e, negative T waves in V4–6/aVL, low voltages in limb leads) or 2) pathology examination of explanted hearts/autoptic cases suffering from sudden cardiac death (SCD). Patients with significant right ventricular involvement were excluded. Results: Sixty-six patients were evaluated for suspected ALVC: 8 phenocopies were excluded (6 acute myocarditis and 2 sarcoidosis) after a comprehensive clinical and multi-modality instrumental evaluation. The final study cohort was composed by 56 patients (55% males, median age 45 years), from 36 families. Diagnostic pathways leading to diagnosis were: SCD in 4 (7%), ventricular arrhythmias in 11 (20%), chest pain in 9 (16%), heart failure in 7 (12%), and familial screening in 25 (45%) (Figure 1). An echocardiogram was available for all but 2 patients with SCD: 25 (46%) had normal phenotype, 17 (32%) had a hypokinetic non dilated cardiomyopathy, and 12 (22%) had a dilated cardiomyopathy (DCM). Of the 49 tested patients, 31 (63%) had a pathogenic/likely pathogenic DNA variant: desmoplakin (DSP, N=21), filamin C (FLNC, N=4), SCN5A (N=3) were the most frequently involved genes; 8 patients had a double gene mutation. Twenty-four patients (43%) had previously received a diagnosis other than ALVC: 10 idiopathic DCM, 9 acute myocarditis, 4 post-myocarditis DCM, 2 acute myocardial injury/non-ST elevated myocardial infarction. In 13 patients ALVC was diagnosed with the introduction of CMR in the diagnostic work-up of a DCM, in 2 cases the diagnosis was done with the pathology examination after heart transplantation. The median diagnostic delay was of 8 years, with a maximum of 20 years. It is worth nothing that patients from the same family might have different diagnostic pathways and phenotypes of ALVC (Figure 2). Conclusions: ALVC is a challenging diagnosis, hidden in different clinical scenarios. Five main clinical pathways leading to ALVC diagnosis may be identified: ventricular arrhythmias, chest pain, heart failure, SCD at first presentation, and clinical/instrumental familial screening. Funding Acknowledgement: Type of funding sources: None.