Development and Validation of a Prediction Model and Score for Transthyretin Cardiac Amyloidosis Diagnosis: T-Amylo.

BACKGROUND Although transthyretin cardiac amyloidosis (ATTR-CA) is often underdiagnosed, clinical suspicion is essential for early diagnosis. OBJECTIVES The aim of this study was to develop and validate a feasible prediction model and score to facilitate the diagnosis of ATTR-CA. METHODS This retrospective multicenter study enrolled consecutive patients who underwent 99mTc-DPD scintigraphy for suspected ATTR-CA. ATTR-CA was diagnosed if Grade 2 or 3 cardiac uptake was evidenced on 99mTc-DPD scintigraphy in the absence of a detectable monoclonal component or by demonstration of amyloid by biopsy. A prediction model for ATTR-CA diagnosis was developed in a derivation sample of 227 patients from 2 centers using multivariable logistic regression with clinical, electrocardiography, analytical, and transthoracic echocardiography variables. A simplified score was also created. Both of them were validated in an external cohort (n = 895) from 11 centers. RESULTS The obtained prediction model combined age, gender, carpal tunnel syndrome, interventricular septum in diastole thickness, and low QRS interval voltages, with an area under the curve (AUC) of 0.92. The score had an AUC of 0.86. Both the T-Amylo prediction model and the score showed a good performance in the validation sample (ie, AUC: 0.84 and 0.82, respectively). They were tested in 3 clinical scenarios of the validation cohort: 1) hypertensive cardiomyopathy (n = 327); 2) severe aortic stenosis (n = 105); and 3) heart failure with preserved ejection fraction (n = 604), all with good diagnostic accuracy. CONCLUSIONS The T-Amylo is a simple prediction model that improves the prediction of ATTR-CA diagnosis in patients with suspected ATTR-CA.Part of this project was funded by Pfizer through an independent general research grant (number 64764667). This study has been partially funded by Instituto de Salud Carlos III through the project "PI20/01379” (co-funded by European Regional Development Fund/ European Social Fund "A way to make Europe"/"Investing in your future"). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa grant (CEX2020-001041-S). Dr Basurte Elorz has received a consultant fee from Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P  Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype