[This corrects the article DOI: 10.1371/journal.pone.0350084.].

BACKGROUND AND OBJECTIVE:Pediatric patients with myocarditis present with heterogeneous symptoms, disease courses and outcomes. Late Gadolinium Enhancement (LGE) in cardiovascular magnetic resonance imaging (CMR) is a routine diagnostic tool, but relationships between LGE patterns and patient characteristics are typically assessed qualitatively. We investigate the use of radiomic features to quantify LGE texture and location to identify signatures that stratify pediatric myocarditis cases. METHODS:We compared radiomic features in a digital phantom across different resampling strategies to address variability in patient size and imaging parameters. Non-negative matrix factorization (NMF) was applied to spatially resolved radiomic features of the left myocardium to identify distinct radiomic signatures in a pediatric cohort with confirmed myocarditis. Clinical parameters were compared across the resulting groups, and correlations between image meta-features and outcomes explored. A user-friendly software tool offers feature extraction and signature calculation on unseen data and comparison of new patients to the existing cohort. RESULTS:The phantom experiments showed improved comparability of radiomic features when resampled to uniform voxel density (voxel count per myocardial diameter) rather than uniform voxel size. After appropriate pre-processing, NMF identified four patient groups with distinct LGE signatures within 195 patients (median age 16 years, 19% female). One group separates out patients with signs of heart failure, correlating with left-ventricular ejection fraction (r=-0.38, 95% CI [-0.50,-0.25]) and log(NT-proBNP) (r=0.36,[0.21,0.50]). A second group's dominant meta-feature correlates with myocardial edema (r=0.27,[0.13,0.40]) and ventricular tachycardia (r=0.19,[0.05,0.32]); a third indicates mild presentation. The clinical relevance of the fourth remains unclear. CONCLUSIONS:Spatially resolved radiomic features from suitably resampled LGE CMR images yield quantitative LGE signatures associated with clinical characteristics in pediatric myocarditis, supporting improved stratification and personalized management in the long run.

Cardiac amyloidosis (CA), a fatal and progressive cardiomyopathy is characterized by amyloid deposition within the myocardium. The main forms of CA include transthyretin amyloidosis (ATTR-CM; distinguished into a hereditary and wildtype form [ATTRv and ATTRwt]) and light-chain amyloidosis (AL). Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is increasingly recognized among heart failure (HF) patients, despite its underestimated prevalence as a rare disease. ATTR-CM is challenging to diagnose due to its broad phenotypic overlap with HF, yet a timely differentiation of CA is crucial, as effective treatment can significantly improve quality of life. Machine learning (ML) approaches could enable earlier detection of ATTR-CM in routine care data. Data of ATTR-CM patients from the Amyloidosis Center Charité Berlin (2002-2023) and data from a cohort with heart failure and aortic stenosis screened for ATTR-CM were mapped from ICD-10-GM to ICD-10-CM and evaluated with an open-source random forest (RF) model based on ICD-10-CM codes which was previously validated in multiple external cohorts in the US and UK. In the cohort of patients with HF and aortic stenosis, cases of ATTR-CM were recognized using the algorithm, although it was not possible to distinguish between ATTRv-CM and ATTRwt-CM. Sensitivity and specificity were significantly lower than in the external validations in the US and UK. Model performance depended strongly on coding granularity and feature availability and contributed to the diminished predictive power. While the RF model showed moderate transferability under enriched conditions, reliance of geographically specific ICD-10 systems limits broader applicability due to coding discrepancies and information loss. These findings underscore the need for improved semantic harmonization of routine data, as well as the integration of rare disease specific ontologies such as the Human Phenotype Ontology (HPO) and ORPHAcodes to enhance cross-border ML-based assistance for timely diagnosing patients with rare diseases.

AIMS:Concomitant aortic stenosis (AS) and cardiac amyloidosis (CA) result in heart failure and reduced life expectancy. Early detection of CA in AS is an unmet clinical need to prevent disease progression. The SAVER study aims to establish a simple CA screening for AS patients. METHODS AND RESULTS:SAVER is a prospective cohort study enrolling AS patients planned for transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). Firstly, patients were assessed for CA-specific symptoms and history on top of AS evaluation. Patients with suspected CA underwent DPD scintigraphy or magnetic resonance imaging. Secondly, we performed multiple-regression analysis to identify optimal parameters for selecting patients at risk of CA. From 2021 to 2023, 1001 patients were enrolled, with 405 (40%) flagged for potential CA. Two hundred six (21%) patients received further diagnostics due to the screening and five (0.5%) patients due to physician discretion, leading to 17 (2%) confirmed CA cases. Key predictors of CA included male sex [OR 23.8 (95% CI 2.6; 216.9)], carpal tunnel syndrome [OR 5.5 (95% CI 1.4; 22.0)], spinal stenosis [OR 4.1 (95% CI 1.1; 14.7)], heaviness or numbness of arms or legs [OR 3.8 (95% CI 1.1; 13.3)], NT-proBNP [OR 6.7 (95% CI 1.8; 25.3)], and sparkling myocardium [OR 4.8 (95% CI 1.3; 17.3)]. The optimized approach reached an AUC of 0.88 (95% CI 0.81-0.96). CONCLUSION:The SAVER approach is the first holistic screening method focusing on CA's multiorgan manifestations in AS. This approach can be implemented in clinical settings to prevent futile outcomes of combined disease.

BackgroundSystemic amyloidosis comprises a heterogeneous group of rare diseases characterised by extracellular deposition of misfolded protein fibrils, leading to progressive organ dysfunction. Due to the variability in clinical presentation and course, collection of system-specific and longitudinal data is essential for understanding disease progression, treatment response and patient outcomes. At the Amyloidosis Center Charité Berlin (ACCB), a prospective amyloidosis registry has been established to systematically collect clinical, laboratory, imaging and patient-reported data with the aim of improving the characterization of the diseases and facilitating translational research.MethodsThis is a single-center prospective registry study that enrols patients diagnosed with systemic amyloidosis. The registry includes demographic data, multidisciplinary clinical phenotyping, biomarkers, biobanking, genetic information, imaging studies, and patient reported outcomes. Here, we describe the standardised protocol for diagnostic workup, baseline and longitudinal data collection, and disease-specific follow-up algorithms. Data will be collected digitally in interoperable data formats to ensure shareability in accordance with GDPR-policies.DiscussionThis registry will serve as a resource for characterizing amyloidosis as a rare disease model in a real-world setting and identifying patterns in disease progression and treatment efficacy. By prospectively collecting high-quality longitudinal data, the study aims to generate insights that can inform clinical decision-making, improve risk stratification and support future intervention studies. In addition, the registry enables collaboration in the discovery of biomarkers and new therapeutic approaches. Ongoing analysis of this cohort will provide a basis for the further development of personalised treatment strategies and the improvement of patient care.Ethics and disseminationEthical approval was given by the local ethic committee. Dissemination of data in publications with different scientific observational and correlational questions is planned. Clinical trial registration: DRKS00032002.

BACKGROUND:Biomarker-based prognostic staging systems, including the National Amyloidosis Centre (NAC) and the Mayo staging systems, are widely-used but have only been validated for treatment-naive patients with cardiac transthyretin amyloidosis (ATTR-CA). OBJECTIVES:The purpose of this study was to assess the accuracy of the NAC and Mayo staging systems in patients with ATTR-CA treated with tafamidis. METHODS:A retrospective observational study following patients with ATTR-CA from initiation of tafamidis (baseline) to time of all-cause death was conducted. Patients were stratified according to the NAC and an adapted Mayo staging system incorporating high-sensitivity cardiac troponin T. Agreement was assessed using weighted Cohen's kappa. The staging systems' ability to identify subgroups with distinct overall survival was assessed using Kaplan-Meier analyses and pairwise log-rank tests. RESULTS:A total of 251 patients with wild-type ATTR-CA treated with tafamidis were followed for a median of 521 (IQR: 262-842) days. There was substantial agreement (weighted kappa = 0.661; P < 0.001) between the NAC and the adapted Mayo staging system. Significant differences in estimated overall survival were observed across all disease stages of the adapted Mayo staging system (I vs II: P = 0.032; I vs III: P < 0.001; II vs III: P = 0.036). Accordingly, estimated overall survival was significantly lower in NAC III compared to NAC I (P < 0.001) and NAC II (P = 0.015). However, there was no significant difference between NAC I and NAC II (P = 0.340). CONCLUSIONS:Both staging systems identified a distinct group of patients with ATTR-CA at the highest risk of death but only the adapted Mayo staging system could accurately distinguish between low- and intermediate-risk patients in the setting of disease-modifying treatment with tafamidis.

Mavacamten ist der erste für die Behandlung von Hypertropher obstruktiver Kardiomyopathie (HOCM) zugelassene Vertreter der sog. Myosininhibitoren. Dargestellt werden die Hintergründe, die aktuelle Studienlage sowie klinische Erfahrungen anhand einer Fallserie zur Real-world-Behandlung mit Mavacamten über einen Zeitraum von 12 Monaten. Es werden Baseline-Charakteristika sowie klinischer und echokardiographischer Verlauf von 11 Patienten, die im Rahmen des Compassionate-use-Programms auf Mavacamten eingestellt wurden, untersucht. Basierend auf den Ergebnissen der beiden Multicenterstudien EXPLORER-HCM und VALOR-HCM wurde Mavacamten im Dezember 2022 in Deutschland für die Behandlung von Patienten mit HOCM zunächst im Rahmen eines Compassionate-use-Programmes zugänglich gemacht, inzwischen besteht eine Zulassung. Wir beschreiben die Erfahrungen mit 11 Patienten, die in diesem Rahmen am Deutschen Herzzentrum der Charité aus klinischer Indikation mit Mavacamten behandelt wurden. Insgesamt bestätigen sich unter Real-world-Bedingungen über 12 Monate die positiven Ergebnisse der Zulassungsstudien.

BACKGROUND: Despite previous histopathologic evidence for its presence, the role of myocardial inflammation in the development and progression of cardiac transthyretin amyloidosis (ATTR-CA) remains insufficiently understood. Thus, this study sought to characterize the prevalence and potential prognostic implications of myocardial inflammation in ATTR-CA. METHODS: A retrospective observational study including patients with ATTR-CA diagnosed by endomyocardial biopsy was conducted. Myocardial inflammation was diagnosed through a review of routine endomyocardial biopsy reports. Baseline characteristics were compared using the Mann-Whitney U test and the Pearson χ 2 test. Clinical outcomes were monitored via follow-up visits or telephone calls. Primary outcomes were all-cause death and a composite end point of all-cause death or heart failure hospitalization. Kaplan-Meier analyses, as well as univariable and age- and sex-adjusted multivariable Cox regression analyses, were used to assess differences in overall and composite end point-free survival between patients with ATTR-CA with and without myocardial inflammation. RESULTS: A total of 103 patients with ATTR-CA (100 wild type; 3 variant) were enrolled. Median follow-up was 18.2 (8.0–31.1) months. Myocardial inflammation was prevalent in 32% (n=33/103) of patients with ATTR-CA. Among evaluable patients with myocardial inflammation, 96% (n=26/27) and 31% (n=9/29) had elevated CD68 (clusters of differentiation 68)–positive macrophage and CD3 (clusters of differentiation 3)–positive T-cell counts, respectively. Overall survival ( P =0.017) and composite end point-free survival ( P =0.014) were significantly impaired in patients with ATTR-CA with myocardial inflammation (n=33) compared with those without (n=70). Statistical significance for both associations was sustained after adjustment for age and sex, yielding adjusted hazard ratios of 4.72 (95% CI, 1.33–16.71; P =0.016) and 2.30 (95% CI, 1.04–5.11; P =0.041) for all-cause death and the composite end point, respectively. CONCLUSIONS: Our findings affirm previous evidence that myocardial inflammation is present in approximately one-third of all patients with ATTR-CA. Moreover, we provide first data indicating that myocardial inflammation may be associated with a higher risk of death and heart failure hospitalizations in ATTR-CA.

Abstract Background Additional cardiac amyloidosis (CA) in severe aortic stenosis (AS) is prevalent in around 8% of AS patients and leads to increased morbidity and mortality. Since both conditions cause comparable symptoms and echocardiographic characteristics of the left ventricle, such as apical sparing and left ventricular wall thickening, diagnosis of CA is challenging in clinical practice. Purpose The present substudy of the SAVER trial aims to compare right heart morphology and function in AS patients with and without additional CA. Methods From 2020 to 2023, AS patients planned for surgical (SAVR) or transcatheter aortic valve replacement (TAVR) with complete echocardiography of the right heart were enrolled in the SAVER study. Transthoracic echocardiography was performed during AS evaluation prior to SAVR or TAVR and, in case of suspected CA, patients underwent further diagnostics including bone scan or MRI. In the present subanalysis, we compared right heart morphology and function of AS patients with and without additional CA as confirmed by bone scan or MRI. Results A total of 28 AS patients were analyzed, including 13 patients with additional CA. The median age was 81±6 years, 75% of patients were male, and 96% were treated with TAVR. Left ventricular wall thickness was comparable between AS patients with and without CA. Regarding right heart morphology and function, AS patients with CA presented a tendency to larger right atrial and ventricular dimension (right atrial area: AS with CA 22 [12-32] mm² vs. AS 17 [8-26] mm²; right ventricular diameter basal: AS with CA 42 [32-52] mm vs. AS 38 [29-47] mm) and a reduced right ventricular function measured by right ventricular fractional area change (AS with CA 37±10% vs. AS 46±11%), right ventricular global (AS with CA -15±6% vs. AS -22±6%) and free wall strain (AS with CA -18±7% vs. AS -19±5%). Right ventricular wall thickness was comparable between both groups and reached 5±1mm. Further echocardiographic parameters are listed in Table 1. Conclusion AS patients with additional CA presented a tendency towards reduced right ventricular function and a more dilated right heart compared to AS patients without CA. These parameters may help to differentiate between both conditions in clinical practice.

AIMS:Myocardial inflammation is increasingly recognized for its association with impaired clinical outcomes in cardiac amyloidosis but a trend towards less invasive diagnosis impedes its detection. The aim of this study was to assess magnetocardiography (MCG) as a potential non-invasive method to diagnose myocardial inflammation in patients with cardiac amyloidosis. METHODS AND RESULTS:This retrospective proof-of-concept study included 27 patients with cardiac amyloidosis who had undergone MCG and endomyocardial biopsy as part of their diagnostic workup. Immunohistopathological evaluation identified myocardial inflammation in 10 patients (37.0%). Patients with myocardial inflammation had significantly higher magnetocardiography vector (VMCG) values than those without (0.093 [IQR 0.058-0.183] vs. 0.052 [IQR 0.039-0.073]; P = 0.01). With an area under the curve of 0.785 (95% CI 0.600-0.970; P < 0.01), VMCG had significant diagnostic value for myocardial inflammation in cardiac amyloidosis when tested against a non-informative random classifier in receiver operating characteristic analysis. Youden's index identified VMCG ≥0.078 as the optimal cut-off to discriminate between patients with and without myocardial inflammation, yielding a sensitivity of 60.0%, a specificity of 88.2%, a positive predictive value of 75.0% and a negative predictive value of 78.9%. CONCLUSIONS:This proof-of-concept study provides initial evidence for the potential of MCG as a non-invasive method to identify myocardial inflammation in patients with cardiac amyloidosis. These findings require validation in larger prospective studies but could substantially contribute to the optimization of personalized management in patients diagnosed with cardiac amyloidosis via non-invasive pathways in the future.

Abstract Background The development of different multiparametric staging systems improved the risk assessment of cardiac transthyretin amyloidosis (ATTR-CA) patients substantially. However, to date, all staging systems were validated in treatment-naive ATTR-CA patients. The introduction of tafamidis led to significant changes in the disease trajectory of ATTR-CA, indicating that it may also have an impact on the prognostic accuracy of these staging systems. Purpose Thus, we sought to assess whether the prognostic value of the National Amyloidosis Centre (NAC) staging system, currently considered as the most accurate, is sustained in ATTR-CA patients treated with tafamidis. Methods This retrospective observational study included ATTR-CA patients treated with tafamidis. Patients were continuously followed from treatment initiation to time of death. NT-proBNP and eGFR data collected at baseline were used to stratify patients into low (stage I), intermediate (stage II) and high-risk (stage III) subgroups according to the NAC staging system. Kaplan-Meier analyses were conducted to illustrate overall survival. Differences in overall survival between subgroups were assessed by log rank tests. P-values <0.05 were considered statistically significant. Results A total of 166 ATTR-CA patients (95.2% wild-type) were enrolled. 81 (48.8%), 51 (30.7%) and 34 (20.5%) patients were stratified into stages I, II and III, respectively. Median follow-up was 539 [323-865] days, during which 20 deaths were recorded. Overall survival of the subgroups over time is demonstrated in figure 1. The probability of overall survival was significantly lower for patients in stage III compared to patients in stages I (log rank; p=0.002) and II (log rank; p=0.031). However, no differences in the probability of overall survival were identified between patients in stage I and II (log rank; p=0.679). Conclusions In this cohort of ATTR-CA patients treated with tafamidis, the NAC staging system effectively identified patients at elevated risk of mortality. However, the distinction in survival rates between low- and intermediate-risk groups was less pronounced, suggesting that tafamidis may have a stronger prognostic impact in these groups.Overall Survival across NAC Stages

Purpose: Myocarditis in pediatric patients can lead to severe heart failure, necessitating ventricular assist devices (VAD) which might serve as a bridge to transplant or as a temporary circulatory support until myocardial recovery. We aimed to identify differences in the clinical and diagnostic findings at initial admission between pediatric patients who could be successfully weaned from VAD and those who could not.

BACKGROUND:Results from ATTR-ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) indicate that tafamidis prolongs survival and reduces cardiovascular hospitalizations in cardiac transthyretin amyloidosis (ATTR-CA). However, real-world data supporting these findings are scarce. Thus, we sought to characterize the clinical outcome of patients with ATTR-CA treated with tafamidis in a real-world setting and assess the prognostic role of the New York Heart Association (NYHA) classification. METHODS AND RESULTS:We conducted a retrospective observational study, enrolling a consecutive sample of patients with ATTR-CA (wild-type or variant) treated with tafamidis. Clinical outcome was tracked through follow-up visits or phone calls. Primary outcomes were death and major adverse cardiac events (MACE), a composite end point of death and hospitalizations for acute cardiac decompensation, myocardial infarction, severe arrythmias, or stroke. Kaplan-Meier analysis estimated overall and MACE-free survival including NYHA subgroups (NYHA I/II versus NYHA III). One hundred sixty-seven patients with ATTR-CA (94.6% wild-type) were enrolled and followed for a median of 539 [323-869] days. Median overall survival was not reached. Estimated 1-year, 2-year, and 5-year overall survival among the whole cohort was 93.5%, 85.9%, and 70.2%, respectively. Overall survival was higher in the NYHA I/II subgroup (P=0.002). Median MACE-free survival time was 1082 (95% CI, 962-1202) days. MACE-free survival was higher in the NYHA I/II subgroup (P<0.001). With respective hazard ratios of 5.85 (95% CI, 1.48-23.18; P=0.012) and 3.95 (95% CI, 1.99-7.84; P<0.001), NYHA III was an independent predictor of death and MACE. CONCLUSIONS:Treatment of ATTR-CA with tafamidis led to substantial improvements of clinical outcome. NYHA classification at treatment initiation is a reliable tool to provide patients with individualized prognostic information.

In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Background/Objectives: Risk assessment in pediatric myocarditis is challenging, particularly when left ventricular ejection fraction (LVEF) is preserved. This study aimed to evaluate LV myocardial deformation using speckle-tracking echocardiography (STE)-derived longitudinal +strain (LS) and assessed its diagnostic and prognostic value in children with myocarditis. Methods: Retrospective STE-derived layer-specific LV LS analysis was performed on echocardiograms from patients within the multicenter, prospective registry for pediatric myocarditis “MYKKE”. Age- and sex-adjusted logistic regression and ROC analysis identified predictors of cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, atrioventricular blockage III°) and major adverse cardiac events (MACE: need for mechanical circulatory support (MCS), cardiac transplantation, and/or cardiac death). Results: Echocardiograms from 175 patients (median age 15 years, IQR 7.9–16.5 years; 70% male) across 13 centers were included. Cardiac arrhythmias occurred in 36 patients (21%), and MACE in 28 patients (16%). Impaired LV LS strongly correlated with reduced LVEF (r > 0.8). Impaired layer-specific LV LS, reduced LVEF, LV dilatation, and increased BSA-indexed LV mass, were associated with the occurrence of MACE and cardiac arrhythmias. In patients with preserved LVEF, LV LS alone predicted cardiac arrhythmias (p < 0.001), with optimal cutoff values of −18.0% for endocardial LV LS (sensitivity 0.69, specificity 0.94) and –17.0% for midmyocardial LV LS (sensitivity 0.81, specificity 0.75). Conclusions: In pediatric myocarditis, STE-derived LV LS is not only a valuable tool for assessing systolic myocardial dysfunction and predicting MACE but also identifies patients at risk for cardiac arrhythmias, even in the context of preserved LVEF.

Background: The spectrum of myocarditis ranges from asymptomatic courses to severe heart failure. Cardiac arrhythmias are another feared complication. The aim of this study is to evaluate initial arrhythmias and their occurrence in the long-term course in pediatric patients with myocarditis to define certain risks.