Accurate assessment of ventricular involvement in transthyretin cardiac amyloidosis (ATTR-CA) is essential for diagnosis and management. This study evaluated left and right ventricular (LV and RV) involvement in patients with ATTR-CA using single-photon emission computed tomography/computed tomography (SPECT/CT) witch Technetium-99m and 3,3-diphosphono-1,2-propanodicarboxylic acid ([99mTc]Tc-DPD).

This prospective, single-centre study enrolled 100 adults from 2020 to 2024 (NCT05814380). Participants underwent clinical assessment, genetic testing, electrocardiography, echocardiography, and [99mTc]Tc-DPD SPECT/CT. Volumetric and regional analyses of LV and RV amyloid burden were conducted. Patients were prospectively observed for 5 years to assess all-cause mortality.

Overall, RV uptake was observed in 91 % of patients with ATTR-CA. Radiotracer uptake was detected in the interventricular septum of all ATTR-CA patients, with apical involvement being less common (24 % hereditary ATTR vs. 31 % wild-type ATTR, p = 0.62). Notably, RV uptake was associated with RV thickness, LV global longitudinal strain, and N-terminal pro-brain natriuretic peptide levels (p = 0.00007, p = 0.00022, p = 0.00007; respectively). Multivariate analysis identified increased LV mass index and NYHA class as predictors of RV involvement (area under curve: 0.96). Volumetric LV and RV SPECT uptake measurements and apical sparing correlated with all-cause mortality (p < 0.001).

The presented findings confirm that SPECT/CT evaluation provides insights into both LV and RV involvement in patients with ATTR-CA and is associated with prognosis. Detailed assessment of RV involvement, through SPECT/CT, reveals significant structural and functional changes associated with disease severity. The presence of RV uptake is associated with advanced cardiac involvement, emphasising the importance of comprehensive biventricular evaluation in this patient population.

The early identification of conditions that lead to increased myocardial wall thickness, such as transthyretin amyloid cardiomyopathy (ATTR-CM), severe aortic stenosis (AS), hypertrophic cardiomyopathy (HCM), and hypertensive heart disease (HHD), is challenging due to overlapping features. Delayed diagnosis can postpone appropriate treatment and worsen prognosis. This study aimed to evaluate the frequency of key electrocardiographic patterns in these conditions, with a specific emphasis on differentiating ATTR-CM from other causes of wall thickening.

Electrocardiograms (ECGs) from the medical records of 400 patients over 60 years old were analyzed, divided into four groups (ATTR-CM, HCM, HHD, and AS) with confirmed diagnoses and septal thickening (≥12 mm). Specific electrocardiographic patterns, including left ventricular hypertrophy, left atrial enlargement, low voltage, pseudoinfarction, and left ventricular pressure overload, were assessed. Multiple chi-square tests with Bonferroni adjustment were used to detect significant differences between groups.

The Sokolow-Lyon criteria was absent in all ATTR-CM cases, compared to 13 % in other conditions (p = 0.001). Additionally, ATTR-CM showed a higher prevalence of low voltage (45 % vs. 18.3 %, p = 0.001) and pseudoinfarction pattern (32 % vs. 22 %, p = 0.007), but a lower prevalence of left atrial enlargement (8 % vs. 30 %, p = 0.005). Absence of the Sokolow criteria was the best predictor of ATTR-CM (sensitivity 100 %, NPV 100 %, PPV 27 %), followed by the presence of low voltage and pseudoinfarction.

Significant differences were observed in the prevalence of electrocardiographic patterns between ATTR-CM and other wall thickening phenotypes. These findings may aid in the early detection and diagnosis of ATTR-CM, allowing for more timely intervention.

Cardiac amyloidosis (CA) is a potentially fatal systemic disease that has received increasing attention in recent years. However, there is no data on its epidemiology in French Guiana. This study aimed to evaluate the epidemiological characteristics of cardiac amyloidosis and describe the regional diagnostic pathways in French Guiana.

We performed a multicenter retrospective study of Guianese patients with confirmed or suspected cardiac amyloidosis who were followed up in hospitals in French Guiana by private cardiologists.

A total of 47 patients were included. The study population was predominantly male (n = 29, 61.7%). The mean age of the population was 72.8 years (SD = 12.2). Most patients were from the island of Cayenne (n = 34, 72.3%), had at least one cardiovascular risk factor (n = 32, 68.1%), and more than half had extracardiac amyloid involvement (n = 25, 53.2%). More than half of the patients were hospitalized at a reference center outside French Guiana (29, 61.7%), mainly at Henri Mondor Hospital (n = 20, 69%) and Martinique (n = 6, 20.7%). Bone scintigraphy was performed in 27 patients (57.5%) and hyperfixation was observed in 25 patients (93%). Anatomopathological examinations were performed in 33 patients (70.2%). Amyloid typing of the biopsied tissue revealed predominantly ATTR (n = 14, 62.6%), AL amyloidosis (n = 1, 4.5%), and AA amyloidosis (4.5%). Among the ATTR amyloidoses, we found mainly ATTRm (n = 22, 75.8%). Genetic mutation testing was performed in approximately half of the patients (n = 25, 51.1%), mostly for the VAL122ILE mutation (n = 21, 84%), and in one case for the IL107VAL mutation (4%). Of the patients with ATTR amyloidosis, 22 (75.9%) were treated with tafamidis. Of the included patients, 18 (38.3%) died. The median overall survival (OS) was 38 months. Survival analysis from the date of diagnosis showed a probability of survival at 30 days, one year, 1.5 years and 4 years of 97% (95% confidence interval [CI]: 90-100), 68% (95%CI 55-84)), 64% (95%CI 51-79)), 32% (95%CI 29-41)), respectively.

This study provides the first information on the diagnostic pathway for cardiac amyloidosis in French Guiana. The increasing proportion of undiagnosed patients has led us to create a French Guianese Amyloidosis Team to simplify the diagnostic pathway by focusing on cardiac MRI and biopsy, which can be performed locally. This is particularly important, as current and future therapeutic advances mean that more effective treatments are on the horizon.

The relevance of repetitive [99mTc]Tc-DPD scintigraphy in wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) remains unclear. We investigated the impact of tafamidis on cardiac [99mTc]Tc-DPD uptake, clinical, and laboratory markers at 6 and 12 months, and correlated 12 months [99mTc]Tc-DPD uptake regression with survival.

This single-center study enrolled 39 ATTRwt-CM patients. Upon treatment initiation with tafamidis, patients underwent follow-up [99mTc]Tc-DPD scintigraphy, and clinical and laboratory evaluations at 6 months (n = 6) and 12 months (n = 13), or both (n = 20).

Tafamidis resulted in a significant decline in Perugini score (6 months p = 0.008, 12 months p < 0.001), and (semi-)quantitative [99mTc]Tc-DPD uptake (total cardiac uptake: baseline 816 [522-933] cps, vs. 6 months 634 [502-734] cps, p = 0.003, vs. 12 months 523 [108-754] cps, p = 0.001). Clinical and laboratory improvements were observed (NYHA: 6 months p = 0.007, 12 months p = 0.033; NT-proBNP: baseline 2586 [1271-5561] ng/L, vs. 6 months 2526 [1109-4786] ng/L, p = 0.016, vs. 12 months 2340 [1411-4749] ng/L, p = 0.012). In Kaplan-Meier analysis, a decrease in right ventricular [99mTc]Tc-DPD tracer uptake equal to or greater than the median value at 12 months (-30%) was associated with improved survival (log-rank p = 0.021).

Tafamidis in ATTRwt-CM resulted in significant reductions of cardiac [99mTc]Tc-DPD uptake, NYHA class, and cardiac biomarkers at 6 and 12 months. Regression of right ventricular [99mTc]Tc-DPD uptake at 12 months was associated with improved survival.

Medical image classification using convolutional neural networks (CNNs) is promising but often requires extensive manual tuning for optimal model definition. Neural architecture search (NAS) automates this process, reducing human intervention significantly. This study applies NAS to [18F]-Florbetaben PET cardiac images for classifying cardiac amyloidosis (CA) sub-types (amyloid light chain (AL) and transthyretin amyloid (ATTR)) and controls. Following data preprocessing and augmentation, an evolutionary cell-based NAS approach with a fixed network macro-structure is employed, automatically deriving cells' micro-structure. The algorithm is executed five times, evaluating 100 mutating architectures per run on an augmented dataset of 4048 images (originally 597), totaling 5000 architectures evaluated. The best network (NAS-Net) achieves 76.95% overall accuracy. K-fold analysis yields mean ± SD percentages of sensitivity, specificity, and accuracy on the test dataset: AL subjects (98.7 ± 2.9, 99.3 ± 1.1, 99.7 ± 0.7), ATTR-CA subjects (93.3 ± 7.8, 78.0 ± 2.9, 70.9 ± 3.7), and controls (35.8 ± 14.6, 77.1 ± 2.0, 96.7 ± 4.4). NAS-derived network performance rivals manually determined networks in the literature while using fewer parameters, validating its automatic approach's efficacy.

Advancements of deep learning in medical imaging are often constrained by the limited availability of large, annotated datasets, resulting in underperforming models when deployed under real-world conditions. This study investigated a generative artificial intelligence (AI) approach to create synthetic medical images taking the example of bone scintigraphy scans, to increase the data diversity of small-scale datasets for more effective model training and improved generalization.

We trained a generative model on 99mTc-bone scintigraphy scans from 9,170 patients in one center to generate high-quality and fully anonymized annotated scans of patients representing two distinct disease patterns: abnormal uptake indicative of (i) bone metastases and (ii) cardiac uptake indicative of cardiac amyloidosis. A blinded reader study was performed to assess the clinical validity and quality of the generated data. We investigated the added value of the generated data by augmenting an independent small single-center dataset with synthetic data and by training a deep learning model to detect abnormal uptake in a downstream classification task. We tested this model on 7,472 scans from 6,448 patients across four external sites in a cross-tracer and cross-scanner setting and associated the resulting model predictions with clinical outcomes.

The clinical value and high quality of the synthetic imaging data were confirmed by four readers, who were unable to distinguish synthetic scans from real scans (average accuracy: 0.48% [95% CI 0.46-0.51]), disagreeing in 239 (60%) of 400 cases (Fleiss' kappa: 0.18). Adding synthetic data to the training set improved model performance by a mean (± SD) of 33(± 10)% AUC (p < 0.0001) for detecting abnormal uptake indicative of bone metastases and by 5(± 4)% AUC (p < 0.0001) for detecting uptake indicative of cardiac amyloidosis across both internal and external testing cohorts, compared to models without synthetic training data. Patients with predicted abnormal uptake had adverse clinical outcomes (log-rank: p < 0.0001).

Generative AI enables the targeted generation of bone scintigraphy images representing different clinical conditions. Our findings point to the potential of synthetic data to overcome challenges in data sharing and in developing reliable and prognostic deep learning models in data-limited environments.

This study aimed to assess the diagnostic accuracy of a novel semiautomated method to calculate relative myocardial wall uptake (RCU) of 99m Technetium-pyrophosphate SPECT/CT in suspected cardiac transthyretin amyloidosis (ATTR).

Prospective analysis of 108 participants with suspected ATTR. Using novel software, we quantified radiopharmaceutical uptake in the wall of each chamber of the heart at 3 h, calculating RCU for combined ventricular (RCU-V) and whole-heart (RCU-W) measures as a ratio over physiological blood-pool activity. Optimal RCU cut-off ratios were determined using a documented clinical diagnosis of ATTR amyloidosis as the reference standard.

The RCU-V method with a cut-off ratio of 1.2 achieved a sensitivity of 100% [95% confidence interval (CI): 90-100%], specificity of 99% (95% CI: 95-100%), and accuracy of 99% (95% CI: 96-100%). The RCU-W method required a higher cut-off ratio of 1.4 to achieve a comparable specificity of 99%.

This novel SPECT/CT quantification software using the RCU-V method significantly improves diagnostic accuracy for cardiac ATTR and represents an advance compared to existing planar nuclear imaging assessment techniques.

Non-invasive right ventricular to pulmonary artery (RV-PA) uncoupling assessment has prognostic value in patients with heart failure (HF). Little is known about its application in patients with wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM). This single-centre retrospective study included consecutive patients with wtATTR-CM diagnosis undergoing 2D echocardiogram. RV-PA uncoupling was evaluated with the ratios between tricuspid annular plane systolic excursion (TAPSE), RV free wall longitudinal strain (RVFWLS) or RV four-chamber longitudinal strain (RV4CLS) and pulmonary artery systolic pressure (sPAP). Primary endpoint was the composite of all-cause mortality and HF hospitalisation. Overall, 100 patients (91% males, median age 81 years, 85% in National Amyloid Centre (NAC) stage ≤ 2, 18% in NAC stage Ia and 82% in New York Heart Association class ≤ II) were enrolled. Over a 16-months follow up (Q1-Q3:12-24), the primary endpoint occurred in 37 patients (37%). TAPSE/sPAP (HR 0.04, 95% CI 0.01-0.24, p < 0.001), RVFWLS/sPAP (HR 0.07, 95% CI 0.01-0.41, p = 0.003) and RV4CLS/sPAP (HR 0.06, 95% CI 0.01-0.53, p = 0.011) emerged as independent predictors of the primary endpoint and showed incremental risk prediction compared with TAPSE, RVFWLS and RV4CLS, considered as separate parameters. No differences in outcome risk prediction were observed among TAPSE/sPAP, RVFWLS/sPAP and RV4CLS/sPAP (p > 0.05). RV-PA uncoupling, as assessed by different echocardiography modalities, is an early predictor of poor outcome in patients with wtATTR-CM.

To investigate the diagnostic performance of computed tomography (CT)-based radiomics in detecting cardiac amyloidosis (CA) in patients with diffuse myocardial thickening.

Patients with diffuse myocardial thickening who underwent coronary CT angiography were retrospectively enrolled from five hospitals. Patients from one hospital were randomly divided into training and internal test cohorts at a 7:3 ratio, and the other four hospitals constituted the external test cohort. The diagnosis of CA followed established guidelines. Regions of interest of myocardium were delineated to extract radiomics features to construct the radiomics model, and myocardial CT attenuation was measured. The diagnostic performance and clinical utility of the radiomics model and myocardial CT attenuation were compared with the area under the curve and decision curve analysis. The correlation between radiomics score and left ventricular function was analysed. A total of 378 patients (median age, 57 years; 257 men) were enrolled. Ten features were selected to construct the radiomics model. The areas under the curve of radiomics model were significantly higher than myocardial CT attenuation in the training (0.95 vs. 0.58, P < 0.001), internal test (0.95 vs. 0.59, P < 0.001), and external test cohorts (0.91 vs. 0.64, P < 0.001). Decision curve analysis indicated the radiomics model provided a greater net benefit than myocardial CT attenuation across cohorts. Radiomics scores were correlated with N-terminal proB-type natriuretic peptide and left ventricular diastolic diameter across cohorts (P < 0.05).

The radiomics model exhibited good diagnostic performance for CA detection in patients with hypertrophic phenotypes, outperforming myocardial CT attenuation.

Background: Bisphosphonate scintigraphy (BS) is a recognized tool for diagnosing amyloid transthyretin cardiomyopathy (ATTR-CA). However, its sensitivity for rare transthyretin (TTR) variants, like Glu54Gln, remains underexplored. Methods: This was a retrospective descriptive study including all known patients with the Glu54Gln variant diagnosed between 2017 and 2023 in Romania, aiming to evaluate the diagnostic performance of BS in Glu54Gln ATTR-CA. Results: All symptomatic patients (n = 22) with histologically confirmed ATTR-CA had positive BS results (100% sensitivity). No false negatives were observed in asymptomatic carriers (n = 4). The Perugini visual score correlated with disease severity, with grade 3 scores associated with advanced cardiac involvement. We proposed a new parameter, heart-to-liver-uptake (H/L) ratio, which proved a strong positive correlation with both the heart-to-contralateral-uptake (H/CL) ratio (R2 = 0.768, p < 0.001) and interventricular septum thickness (R2 = 0.584, p < 0.001) and a weak correlation with the global longitudinal strain (R2 = 0.212, p = 0.023). Conclusions: BS demonstrates high diagnostic accuracy for Glu54GlnATTR-CA, underscoring its utility in early diagnosis and clinical management. The H/L ratio presents a novel approach to semiquantitative analysis of bisphosphonate uptake in cardiac amyloidosis, potentially addressing key limitations of the traditional H/CL ratio.

Background: Carpal tunnel syndrome (CTS) has emerged as an early indicator of cardiac amyloidosis (CA) caused by transthyretin-associated (ATTR) mutations, possibly linked to adverse cardiovascular outcomes. This case series examines the relationship between idiopathic CTS and CA imaging diagnosis. Methods: Twenty-two patients from the cross-sectional study CarPoS (NCT05409833) were included. These patients underwent physical evaluation, laboratory exams, electrocardiography, echocardiography, cardiac magnetic resonance (CMR) imaging, and scintigraphy with 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Results: Four of the twenty-two patients included had ATTR cardiomyopathy. These patients presented left-ventricle hypertrophy and signs of infiltrative cardiomyopathy in echocardiograms and late gadolinium enhancement in CMR images without having any cardiovascular symptoms. Conclusions: Our findings suggest a high prevalence of CA in patients with bilateral idiopathic CTS, highlighting the importance of screening for CA in patients with CTS. Early detection could significantly impact patient prognosis, underscoring the need for further research into diagnostic and therapeutic strategies.

To apply the American College of Cardiology (ACC) and American Heart Association (AHA) heart failure (HF) staging system to patients with transthyretin cardiac amyloidosis (TTR-CA) in order to assess diagnostic delay and evaluate prognosis.

Consecutive patients with TTR-CA enrolled in an Italian registry were classified according to the ACC/AHA HF staging system at diagnosis. Outcome was assessed as all-cause mortality during a 3-year follow-up.

At diagnosis, of 549 patients with TTR-CA, 115 (20.9%) presented with HF stage B, 172 (31.3%) with stage C1, 198 (36.1%) with stage C2, and 64 (11.7%) with stage D. Patients with stages B, C1, C2, and D presented with hierarchically higher prevalence of left ventricular systolic impairment, advanced diastolic dysfunction, advanced New York Heart Association functional class, hospitalization for HF, and N-terminal pro-B-type natriuretic peptide values. At 3 years, the survival rate was 94% in patients with stage B HF, decreasing to 69% with stage C1, 43% with stage C2, and 17% with stage D. At multivariable analysis, considering stage B as the reference, risk increase for all-cause mortality was 4, 5, and 11 for stages C1, C2, and D, respectively.

At diagnosis, almost half of patients with TTR-CA present with advanced stages of HF (C2 or D), suggesting marked diagnostic delay. The ACC/AHA HF staging system accurately stratifies prognosis and may be usefully added to the multiparametric evaluation of patients with TTR-CA.

To determine whether TTRv carriers with Perugini grade 1 cardiac radiotracer uptake on [99mTc]Tc- hydroxydiphosphonate bone scintigraphy have or develop ATTR-CM.

This retrospective observational study was conducted at the Groningen Amyloidosis Centre of Expertise between April 2012 and June 2023. TTRv carriers with Perugini grade 1 uptake on bone scintigraphy were followed until to June 2024. Data on symptoms, biomarkers, imaging, and biopsies were collected. A descriptive analysis was performed to evaluate whether carriers met the diagnostic criteria for ATTR-CM or 'probable ATTR-CM' at baseline and follow-up.

Out of 178 TTRv carriers in screening, 12 carriers had Perugini grade 1 cardiac radiotracer uptake on bone scintigraphy. At baseline, 2 carriers met the diagnostic criteria for ATTR-CM and 3 carriers met the criteria for probable ATTR-CM. Of the 7 carriers without (probable) ATTR-CM at baseline, 3 carriers were diagnosed with ATTR-CM during follow-up and 1 carrier developed probable ATTR-CM during follow-up. Three carriers showed signs of cardiomyopathy during follow-up, but did not meet the criteria for (probable) ATTR-CM. One of these cases may have been false-positive due to hydroxychloroquine use.

Our findings suggest that Perugini grade 1 cardiac radiotracer uptake is an early marker of ATTR-CM in TTRv carriers, potentially enabling earlier diagnosis and intervention.

Cardiac amyloidosis is characterized by systolic and diastolic abnormalities due to deposition of amyloid fibril within the myocardial extracellular space. Technological advances in multimodality cardiac imaging now helps in accurate diagnosis and prognosis of this disease. With technological advances in imaging, it is now easier to follow up these patients whether they are getting response to therapy.

Left ventricular global longitudinal strain assessment is an important noninvasive tool to track response to treatment in cardiac amyloidosis patient.

Present era has shown the importance of using multimodality imaging to understand the pathophysiology of this disease which has been supplemented by both imaging and blood biomarkers. These help in prognosticating the disease burden and to assess treatment response. Future research is now focused on the use of artificial intelligence and precision medicine to detect of changes earlier in the course of treatment.

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease that has emerged as a significant cause of heart failure. Advances in the understanding of ATTR-CM pathophysiology have revolutionised its therapeutic landscape over the past decade, with the development of targeted therapies that are able to improve survival and quality of life. TTR stabilizers, such as tafamidis and acoramidis, can reduce TTR instability and subsequent amyloid fibril formation. Clinical trials have demonstrated their efficacy both in improving survival and quality of life in patients with ATTR-CM. Gene-silencing therapies using small interfering RNAs (siRNAs), such as patisiran and vutrisiran, or antisense oligonucleotide inhibitors (ASOs), such as inotersen and eplontersen, serve as powerful therapeutic options by decreasing TTR production; trials on patients with ATTR-CM have been recently published or are ongoing. Novel, emerging therapies aim to enhance fibril clearance using monoclonal antibodies, such as NI006, that target amyloid deposits in the myocardium, promoting their depletion, plausibly with regression of the structural and functional impairments caused by the disease. Concurrently, advancements in diagnostic modalities have facilitated earlier detection of this disease, allowing the timely initiation of treatment with a more significant impact on patients' survival and quality of life. Despite these strides, challenges remain, including the high cost of disease-modifying therapy and the need for response criteria to monitor treatment's efficacy. Future directions will involve improving patients' screening to achieve earlier diagnoses, optimising patients' selection for disease-modifying therapy and identifying criteria for the treatment's response or lack thereof to possibly consider therapy switch or associations. In this review, we will explore the more recent therapeutic advancements in ATTR-CM, starting from traditional heart failure therapies and moving to disease-modifying therapies with a detailed evaluation of the registration trials to explore the strengths and shortcomings of each treatment.

Background/Objectives: In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), the effect of tafamidis on right ventricular (RV) dysfunction has been poorly investigated. The purpose of this study was to evaluate the effect of tafamidis on RV free wall global longitudinal strain (RV FW-GLS) and right ventricular and pulmonary artery (RV-PA) coupling over 12 months of treatment. Methods: Ninety-three patients with ATTR-CM treated with 61 mg of tafamidis daily who underwent multimodality imaging evaluation at baseline by cardiovascular magnetic resonance (CMR) and speckle-tracking echocardiography were retrospectively studied. The 12-month follow-up included an echocardiographic assessment of RV FW-GLS and RV-PA coupling. RV reverse remodeling was defined as a >10% improvement in RV FW-GLS and/or in RV-PA coupling from baseline. RV-PA coupling was assessed using the tricuspid annular plane systolic excursion/ pulmonary artery systolic pressure (TAPSE/PASP) ratio. Results: Over 12 months of tafamidis treatment, RV reverse remodeling was documented in 22.6% of patients. In these patients, RV FW-GLS improved significantly from 14.5 ± 2.1% to 17.3 ± 2%, p < 0.001, whereas the TAPSE/PASP ratio improved from 0.42 ± 0.05 mm/mmHg to 0.54 ± 0.07 mm/mmHg, p = 0.001. Patients who experienced RV reverse remodeling were at an earlier stage of disease prior to tafamidis treatment with less dilated RV and less severe RV-PA uncoupling (TAPSE/PASP ratio: 0.43 ± 0.06 mm/mmHg vs. 0.39 ± 0.06 mm/mmHg, p = 0.040). CMR-derived baseline RV end-systolic volume (HR 0.83, 95% CI 0.73-0.94, p = 0.005) and NT-proBNP (HR 0.989, 95% CI 0.988-0.999, p = 0.024) were the strongest independent predictors of RV reverse remodeling, followed by PASP (HR 0.82, 95% CI 0.69-0.98, p = 0.030). Conclusions: Patients with ATTR-CM treated with tafamidis at an earlier stage of the disease experienced RV reverse remodeling with significant improvement in RV FW-GLS and RV-PA coupling.

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.

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.

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<0.001, respectively). The best hs-cTnI threshold for 18-month mortality of the combined Abbott/Beckman cohorts (n=234) was 81 ng/L, rounded to 80 ng/L for simplicity of clinical use. A 2-variable staging system (based on the Mayo Clinic system) using hs-cTnI (>80 ng/L) and NPs (natriuretic peptides, NT-proBNP [N-terminal pro-B-type NP] >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.

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.

Wild-type transthyretin cardiac amyloidosis (ATTRwt CA) is increasingly recognized as an important cause of heart failure and arrhythmias in older people. There are several clinical, echocardiographic, electrocardiographic (ECG) and laboratory features that increase the suspicion for ATTRwt CA. Presentation and phenotype can, however, be associated with atypical findings making it difficult to make a correct diagnosis. A 65-year-old man was admitted for an acute coronary syndrome. Echocardiography revealed diffuse concentric left ventricular (LV) thickening. Because of a history of bilateral carpal tunnel syndrome and polyneuropathy, the patient underwent dedicated laboratory testing and diphosphonate scintigraphy the results of which were suggestive of transthyretin cardiac amyloidosis. Also, a dynamic LV outflow tract obstruction due to the systolic anterior motion of the anterior mitral valve was noted on echocardiography during the initial investigations. Genetic testing for hypertrophic cardiomyopathy was negative. Seeking a conclusive diagnosis, endomyocardial biopsy was performed. This confirmed the diagnosis of ATTRwt CA.

The presence of dynamic LV outflow tract obstruction is typically seen in patients with sarcomeric hypertrophic cardiomyopathy. It can be rarely seen also in individuals with cardiac amyloidosis, including ATTR-wt CA. The presence of so-called red flags in patients' history, physical examination, laboratory test, ECG and imaging should raise suspicion for other etiologies of LV wall thickening than hypertrophic cardiomyopathy. Although noninvasive diagnosis of ATTRwt CA is possible in most patients, endomyocardial biopsy remains necessary in cases with diagnostic ambiguity.

BackgroundAmyloid deposition manifests as thickening and calcification of the joints on computed tomography (CT) images.PurposeTo investigate the diagnostic potential of thickening and calcification of the shoulder and hip joints for the detection of transthyretin amyloid cardiomyopathy (ATTR-CM).Material and MethodsWe included 19 patients who had been assessed using 99mTc-pyrophosphate scintigraphy between January 2019 and December 2022 and diagnosed with ATTR-CM. The incidence of calcification and synovial thickening in the hip and shoulder joints of the patients and controls was evaluated. Two radiologists determined differences in joint calcification and thickness on CT images using Pearson chi-square tests and unpaired t-tests, respectively.ResultsShoulder and hip joint thickness (both P < 0.01) and calcifications (P < 0.05) significantly differed between the groups. The area under the receiver operating characteristic curve (AUC) was 0.74 for the shoulder joint, and the cut-off Youden index was 16.1 mm, with a sensitivity and specificity of 63.2% and 78.9%, respectively. The AUC was 0.844 for the hip joint, with an optimal cutoff of 11.8 mm, with a sensitivity and specificity of 71.4% and 89.5%, respectively. Inter-observer agreement was substantial between the radiologists for detecting hip and/or shoulder joint calcification (κ = 0.712). The interclass correlation coefficients (2, 1) were 0.65 and 0.71 for measurements of shoulder and hip joint thickness, respectively.ConclusionThickened and calcified shoulder and hip joints are more likely to be found in patients with clinically diagnosed ATTR-CM than those without.

Transthyretin-related cardiac amyloidosis (ATTR-CA) is often diagnosed at an advanced stage. Emerging evidence suggests that radiomics applied to echocardiographic images (ie, ultrasonomics) can detect early myocardial texture changes in ATTR-CA.

This study aimed to develop a radiomic model for characterizing ATTR-infiltrated myocardium via echocardiography.

Echocardiographic images in parasternal long-axis and apical 4-chamber views from ATTR-CA and control patients were collected across 4 Italian centers. A region of interest (ROI) within the interventricular septum was delineated. Ninety-four radiomic features were extracted and classified into 2 categories for analysis, based on whether they were ROI-dependent or independent. Five logistic regression models analyzed data from 3 centers (229 ATTR-CA, 224 controls) to assess diagnostic accuracy and area under the curve (AUC) of different sets of radiomic features, with external validation conducted on patients from a fourth center (32 ATTR-CA, 32 controls).

Models analyzing the entire ROI using both ROI-dependent and ROI-independent features demonstrated high cross-validated accuracies (93%-95%) and AUC values (0.97-0.99). Using a fixed-size 0.5 × 0.5 cm ROI, these values decreased to 85% and 0.91, respectively, highlighting previous models' dependence on ROI size. The fifth model used 73 ROI-independent features on the entire ROI and demonstrated significantly better accuracy and AUC (92% and 0.97, respectively, P < 0.001), confirmed in the external validation cohort (87% and 0.95, respectively). Removing the least informative features slightly improved the model, achieving 90% accuracy and 0.95 precision.

This study showcases ultrasonomics potential to differentiate ATTR-CA and control patients by capturing disease-specific textural features independent of ROI dimensions.

Amyloidosis is a multisystem disease characterized by the deposition of amyloid fibrils, leading to organ dysfunction. When cardiac amyloidosis is suspected, it is essential to screen for light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR), the two most common subtypes.

We report a patient with advanced heart failure and mild kidney dysfunction as initial symptoms. Preliminary testing revealed a slightly abnormal light chain ratio and a strong positive Tc-99 m pyrophosphate (PYP) scan. Biopsies of the heart, bone marrow, and kidney confirmed amyloidosis. Further immunofluorescence and mass spectrometry analysis identified immunoglobulin G and lambda light chain deposits. The patient was diagnosed with multiple myeloma and heavy and light chain amyloidosis (AHL) and initiated treatment with cyclophosphamide, bortezomib, and dexamethasone, rather than tafamidis, an oral transthyretin kinetic stabilizer used for ATTR.

AHL amyloidosis is a rare subtype. This case demonstrates that a positive PYP scan, even with intense uptake, is not entirely specific for ATTR. Tissue confirmation is essential for a definitive diagnosis, particularly when light chain disease or other rare forms are suspected, because AL/AHL and ATTR have distinct treatments and prognoses and may coexist.

Light chain amyloidosis and transthyretin amyloidosis are rare protein misfolding disorders characterized by amyloid deposition in organs, varied clinical manifestations, and poor outcomes. Amyloid fibrils trigger various signaling pathways that initiate cellular, metabolic, structural, and functional changes in the heart and other organs. Imaging modalities have advanced to enable detection of amyloid deposits in involved organs and to assess organ dysfunction, disease stage, prognosis, and treatment response. The Amyloidosis Forum hosted a hybrid meeting to focus on the use of imaging endpoints in clinical trials for systemic immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Stakeholders from academia and industry, together with representatives from multiple regulatory agencies reviewed the use of imaging biomarkers with a focus on cardiac amyloidosis, described applications and limitations of imaging in clinical trials, and discussed qualification of imaging as a surrogate clinical outcome. Survey results provided important patient perspectives. This review summarizes the proceedings of the Amyloidosis Forum.

Recent advances in the management of transthyretin amyloid cardiomyopathy (ATTR-CM) have highlighted the need for early identification. Studies have demonstrated amyloid deposits in orthopedic surgical specimens, prompting a diagnosis of concurrent ATTR-CM. We sought to determine the prevalence of spinal amyloid deposits among patients undergoing spinal stenosis decompression surgery and whether the presence of deposits was associated with ATTR-CM.

Patients >60 years of age undergoing spinal stenosis decompression surgery were enrolled as part of a prospective, single-center, cohort study. Samples from the disc and ligamentum flavum were obtained during surgery. Patients with amyloid deposition on Congo red staining returned for standard-of-care clinical assessment consisting of blood testing, a transthoracic echocardiogram, nuclear pyrophosphate imaging when indicated, and an evaluation with a cardiologist.

Out of 54 enrolled patients, 24 patients (44%; 95% CI, 31%-59%) were found to have spinal amyloid deposits. Amyloid-positive patients were older than amyloid-negative patients (70 years vs. 63 years, p < 0.01). On follow-up testing, no amyloid-positive patients were found to have definitive ATTR-CM. However, 37% of amyloid-positive patients had abnormal cardiac biomarkers, and 36% of amyloid-positive patients had reduced global longitudinal strain on echocardiography, suggesting possible early disease.

Spinal amyloid deposits, in both the disc and ligamentum flavum, were found in 44% of older patients undergoing spinal stenosis decompression surgery. While none of these patients tested positive for ATTR-CM on early follow-up, subtle abnormalities in cardiac testing suggest that further follow-up testing is warranted to detect the advent of cardiac amyloidosis in the future.

Advancements in knowledge of cardiovascular disease, pharmacology, and chemistry have led to the development of newer radiopharmaceuticals and targets for new and more suitable molecules. Molecular imaging encompasses multiple imaging techniques for identifying the characteristics of key components involved in disease. Despite its limitations in spatial resolution, the affinity for key molecules compensates for disadvantages in diagnosing diseases and elucidating their pathophysiology. This review introduce established molecular tracers involved in clinical practice and emerging tracers already applied in clinical studies, classifying the key component in A: artery, specifically those vulnerable plaque (A-I) inflammatory cells [18F-FDG]; A-II) lipid/fatty acid; A-III) hypoxia; A-IV) angiogenesis; A-V) protease [18F/68Ga-FAPI]; A-VI) thrombus/hemorrhage; A-VII) apoptosis and A-VIII) microcalcification [18F-NaF]) and B: myocardium, including myocardial ischemia, infarction and myocardiopathy (B-I) myocardial ischemia; B-II) myocardial infarction (myocardial damage and fibrosis); B-III) myocarditis and endocarditis; B-IV) sarcoidosis; B-V) amyloidosis; B-VI) metabolism; B-VII) innervation imaging). In addition to cardiovascular-specific tracers tested in animal models, many radiotracers may have been developed in other areas, such as oncology imaging or neuroimaging. While this review does not cover all available tracers, some of them hold potential for future use assessing cardiovascular disease. Advances in molecular biology, pharmaceuticals, and imaging sciences will facilitate the identification of precise disease mechanisms, enabling precise diagnoses, better assessment of disease status, and enhanced therapeutic evaluation in this multi-modality era.

The increasing recognition of cardiac amyloidosis (CA) as a cause of heart failure, coupled with advancements in therapeutic options, has underscored the need for early detection. Positron emission tomography (PET) imaging emerged as a promising non-invasive tool for diagnosing and managing CA. This review provides a comprehensive analysis of current PET imaging techniques, focusing on radiotracers, including [11C]Pittsburgh Compound B, [18F]Flutemetamol, [18F]Florbetapir, [18F]Florbetaben, [18F]-sodium fluoride, and [124I]Evuzamitide. PET imaging's ability to differentiating CA subtypes and quantify amyloid burden contributes defining prognosis and aids in monitoring treatment response. However, standardizing imaging protocols and establishing definitive diagnostic thresholds remain challenging. As PET imaging continues to evolve, it promises to improve patient outcomes by facilitating earlier diagnosis, more accurate subtype differentiation, and better treatment monitoring in CA.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) occurs at a high prevalence in older patients with left ventricular (LV) hypertrophy. However, detecting ATTRwt-CA using echocardiography is challenging.

This study identified echocardiographic findings characterizing ATTRwt-CA compared with monoclonal immunoglobulin light chain cardiac amyloidosis (CA) and hereditary transthyretin CA.

We conducted a multicenter, retrospective study on the echocardiographic findings characterizing ATTRwt-CA. J-CASE (Japan Cardiac Amyloidosis Survey of typical Echocardiographic findings) analyzed echocardiographic data in 311 patients with histologically proven amyloid deposition in the myocardium and diagnosis of transthyretin CA or monoclonal immunoglobulin light chain CA.

Among the cohort, 172 patients (55.3%) were diagnosed with ATTRwt-CA. A multiple discriminant analysis revealed that LV hypertrophy with a more extensive LV mass index but relatively modest interventricular septum thickening and enlargement of maximal papillary muscle diameter were significant echocardiographic findings characterizing ATTRwt-CA. In addition to the patient backgrounds such as advanced age, male sex, concomitant diabetes mellitus, hyperlipidemia, carpal tunnel syndrome, and paroxysmal atrial fibrillation, the discriminant model, including these echocardiographic findings showed significant discriminant power of ATTRwt-CA from the other subtypes (83.8% accuracy with 86.0% positive predictive value and 81.4% negative predictive value, when the sensitivity and specificity are at their maximum values of the model).

In the J-CASE data set, LV hypertrophy with a more extensive LV mass index but relatively modest interventricular septum thickening and enlargement of papillary muscle diameter significantly characterized ATTRwt-CA. These findings may lead to more accurate screening echocardiography for diagnosing ATTRwt-CA and motivate the subsequent comprehensive clinical diagnostic process, including multimodality imaging.

Transthyretin cardiac amyloidosis (ATTR-CA) leads to myocardial infiltration, affecting prognosis and survival. Diagnosing early-stage ATTR-CA remains challenging due to its subtle manifestations. This study investigates subclinical myocardial alterations in asymptomatic ATTR mutation carriers (ATTR-MC) using advanced cardiac magnetic resonance (CMR) techniques, including T1 mapping and myocardial strain analysis. A retrospective cohort of 60 subjects was analyzed, comprising 20 ATTR-CA patients, 20 asymptomatic ATTR-MC, and 20 controls. Standard CMR parameters were compared alongside myocardial strain analysis. Results indicated that despite preserved ejection fraction and myocardial morphology, ATTR-MC exhibited significantly impaired left ventricular global longitudinal strain (LV GLS), left atrial reservoir, conduit, and booster pump strain (LA RS, CS, and BPS) compared to controls. However, native T1 and extracellular volume (ECV) values remained within normal ranges, distinguishing early dysfunction from overt amyloid deposition seen in ATTR-CA. These findings suggest that myocardial strain analysis could serve as an early biomarker for subclinical ATTR-CA, offering a potential target for selecting patients who may benefit from early intervention. Implementing CMR-derived strain parameters in clinical practice may improve risk stratification and timely therapeutic decisions in ATTR-MC.

Patients with transthyretin (ATTR) cardiac amyloid infiltration are increasingly diagnosed at earlier disease stages with no heart failure (HF) symptoms and a wide range of cardiac amyloid infiltration.

To characterize the clinical phenotype and natural history of asymptomatic patients with ATTR cardiac amyloid infiltration.

This cohort study analyzed data of all patients at 12 international centers for amyloidosis from January 1, 2008, through December 31, 2023. Inclusion criteria were asymptomatic ATTR cardiac amyloid infiltration, defined as an absence of HF history, HF signs and symptoms, diuretic therapy, and plasma cell dyscrasia with evidence of myocardial uptake on bone scintigraphy. If plasma cell dyscrasia was present, histologic confirmation of ATTR amyloid was required.

Asymptomatic ATTR cardiac amyloid infiltration.

The primary outcomes were all-cause and cardiovascular (CV) mortality. The secondary outcomes were unplanned HF hospitalization, unplanned CV-related hospitalization, and a composite outcome of CV mortality and HF hospitalization.

The study comprised 485 patients with asymptomatic ATTR cardiac amyloid infiltration (mean [SD] age, 74.9 [9.9] years, 85.8% male, 112 [23.1%] with hereditary ATTR amyloidosis), with 369 (76.1%) having grade 2 or 3 and 116 (23.9%) having grade 1 cardiac uptake at baseline. Patients with grade 2 or 3 uptake exhibited significantly more cardiac functional and structural abnormalities vs patients with grade 1 uptake. At 3 years, compared with grade 1 uptake, patients with grade 2 or 3 uptake had greater development of HF (54.3% [95% CI, 47.7%-61.3%] vs 23.1% [95% CI, 14.8%-35.1%]), greater outpatient diuretic initiation and N-terminal pro-B-type natriuretic peptide progression (35.0% [95% CI, 28.0%-43.2%] vs 12.4% [95% CI, 6.3%-23.7%]), and greater HF hospitalization (8.7% [95% CI, 5.9%-12.9%] vs 0%) and unplanned CV hospitalization (20.0% [95% CI, 15.7%-25.3%] vs 4.3% [95% CI, 1.6%-11.3%]). Over a median follow-up of 37 months (IQR, 20-64 months), the all-cause death rate was similar between patients with grade 1 vs 2 and 3 uptake; however, those with grade 2 or 3 compared with grade 1 uptake had a significantly higher risk of CV mortality (unadjusted hazard ratio, 5.30; 95% CI, 1.92-14.65).

This study shows that asymptomatic ATTR cardiac amyloid infiltration encompasses a wide spectrum of disease severity, with patients with grade 2 or 3 cardiac uptake experiencing an increased rate of CV events and CV mortality and patients with grade 1 uptake experiencing a lower CV event rate and predominantly non-CV mortality. These findings support the use of disease-modifying treatments in asymptomatic patients with grade 2 or 3 uptake and highlight the need of large-scale studies to assess their role in grade 1 uptake.