Transthyretin-related Amyloidosis Research Articles

Bone Scintigraphy in Cardiac Transthyretin-Related Amyloidosis: A Novel Time-Saving Tool for Semiquantitative Analysis, with Good Potential for Predicting Different Etiologies

(1) Background: The visual and semiquantitative analysis of Technetium-99metastable-3,3-diphospono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphy is promising for diagnosing cardiac amyloidosis but time-consuming. We validated a faster method, the geometric mean (GM) method with a semi-automated workflow, for heart–whole body (WB) ratio (H/WBr), heart retention (Hr), and WB retention (WBr) calculations compared to the classic method (CM) established in the literature. The capability of semiquantitative scintigraphy indexes to differentiate the etiology in transthyretin-related cardiac amyloidosis (cATTR) patients was investigated. (2) Methods: H/WBr, Hr, and WBr were calculated by extracting counts for WB, kidneys, bladder, and heart on early and late planar image scans and applying background, scan-time, and decay corrections, using CM and GM both on a referring workstation and on a semi-automated workflow in external software. The comparison between CM and GM was assessed with Pearson’s correlation, Lin’s Concordance Correlation Coefficient (CCC), and Bland–Altman analysis. H/WBr, Hr, and WBr and several clinical variables were used to implement LASSO, Random Forest (RF), and Neural Network (NN) models to predict mutated and wild-type ATTR etiologies. ROC curves and AUC were calculated. (3) Results: Hr, WBr, and H/WBr using CM and GM were highly correlated. Bland–Altman analysis between CM and GM showed biases of 0.12% [CI:0.04%;0.19%] for H/WBr, 0.07% [CI: 0.01%; 0.13%] for Hr, and -0.50% [CI: −1.22%; 0.22%] for WBr. LASSO and NN models had good performance in predicting etiologies with AUC values of 87.3% and 73.6%, respectively. The RF model showed a poorer AUC of 55.8%. (4) Conclusions: The GM in the assisted workflow was validated against the CM. LASSO and NN approaches allowed a good prediction performance to be obtained for patient etiology.

Cardiac amyloidosis: a texture issue. a proof of concept study on quantification of granular sparkling in patients with transthyretin-related cardiac amyloidosis using radiomics and granulometry

Abstract Background Granular sparkling is a well-known echocardiographic feature found in patients with transthyretin-related cardiac amyloidosis (ATTR-CA). However, there is no objective technique for quantifying this feature, which therefore remains a qualitative, elusive and ultimately unreliable imaging characteristic. Recent evidence suggests that radiomics and, in particular, ultrasonomics could play an important role in the non-invasive tissue characterization of cardiomyopathies through the study of specific myocardial texture features. Purpose The aim of this study is to statistically and geometrically characterize granular sparkling as a volume-independent texture property of the myocardium in patients with ATTR-CA. Methods We retrospectively collected echocardiogram video-clips in parasternal long axis (PLAX) and 4-chamber (4CH) views of 229 patients with ATTR-CA, and 224 age- and gender-matched hypertensive patients without any known cardiac disease. From each video-clip, one end-diastole frame was extracted and annotated by an expert to identify a region-of-interest (ROI) within the interventricular septum. Left ventricle chamber masks were also extracted, and used as a brightness reference to enforce invariance w.r.t. the settings of the specific ultrasound system (Fig. 1). Because many established radiomic textural features are heavily volume-confounded, we analyzed the ROI texture by extracting a subset of volume-invariant radiomic features (i.e. ROI-independent), as well as morphological granulometry features. We then fitted a logistic regression classifier to discriminate between ATTR-CA and controls based on the computed textural features. Results 94 radiomic features were identified, of which 73 were volume-invariant. The texture-based classifier predicted the diagnosis with a cross-validated accuracy of 91%, a specificity of 90% and a sensitivity of 92% by utilizing 73 volume-invariant radiomic features on both PLAX and 4CH views (Fig. 2). The addition of granulometry and the further addition of 11 volume-confounded features and 9 shape features to the model did not significantly enhance its discriminative performance (Fig. 2). The top 10 volume-invariant discriminative features were largely consistent in PLAX and 4CH views (Fig. 2), with variables descriptive of greater heterogeneity (such as glszm_ZoneEntropy and glszm_RunEnNtropy) and a higher spatial rate of change (such as ngtdm_Complexity) in the texture of ATTR-CA frames as compared to control frames. Conclusions Our results confirm the ability of radiomics in detecting subtle differences in the myocardial texture of echocardiographic images between patients with ATTR-CA and hypertensive controls. High levels of accuracy are obtained with a purely texture-based, volume-independent set of features. These findings suggest that the diagnosis of ATTR-CA could be simplified and made earlier using a statistical model based on the extraction of radiomic features.Figure 1Figure 2

Hereditary Transthyretin-Related Amyloidosis Ongoing Observational Study: A Baseline Report of the First 3167 Participants.

Background: Hereditary transthyretin-related amyloidosis is a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene (hATTR amyloidosis). Objective: The current study describes the demographic, clinical, and genetic characteristics of patients with suspected hATTR amyloidosis. Methods: This study is part of the "Hereditary transthyretin-related amyloidosis and longitudinal monitoring of TTR-positive patients" (TRAMmoniTTR) study. This study included 3167 participants, along with their clinical details. Principal component (PC) analysis was used to analyze their clinical symptomatology. Next-generation sequencing of the TTR gene was performed and genotype-phenotype relationships were investigated. We compared the demographic and clinical characteristics using the principal components (PCs) and also compared participants with and without the TTR pathogenic variants. Results: We identified five main clinical phenotypes out of 22 single symptoms that explained 49% of the variation. The first two PCs referred to polyneuropathy and cardiomyopathy. We found significant differences between gender and PC-polyneuropathy and PC-cardiomyopathy, with male over-representation in the higher quantiles of PC-polyneuropathy and male under-representation in the lowest quantiles of PC-cardiomyopathy. We identified 92 participants with hATTR (3%), exhibiting 17 unique heterozygous TTR variants. The p.Val50Met variant was the most frequent. Furthermore, 503 participants (20%) were identified with ATTR and no relevant TTR variants (ATTRwt). We detected significant differences between the ATTRwt and hATTR groups, with male gender predominance in only the ATTRwt group and a positive family history of polyneuropathy and/or cardiomyopathy among the hATTR participants. Conclusions: The current clinical and genetic characterization of this cohort serves as a foundation for further longitudinal monitoring and assessment.

Clinical outcomes for 2788 patients with transthyretin amyloidosis: Tafamidis meglumine early access program in France

BackgroundEarly access experience in France with tafamidis meglumine, a selective transthyretin stabilizer for transthyretin-related amyloidosis cardiomyopathy (ATTR-CM), following transthyretin-related amyloidosis (ATTR) polyneuropathy approval and positive ATTR-ACT study results. AimTo describe the characteristics and clinical outcomes for patients in the French ATTR-CM tafamidis meglumine early access programme (28 Nov 2018 to 01 Jun 2021). MethodsPatients with confirmed ATTR-CM received tafamidis meglumine 20mg/day or 80mg/day. Demographic and clinical data were collected prospectively until patients discontinued treatment or died, or the programme ended. ResultsOverall, 222 physicians from 126 centres enrolled 2788 patients. The median age was 82years, 81.6% were male and New York Heart Association severity was class I for 12.8%, class II for 60.1% and class III for 27.0%. Overall, 1943 (74.6%) had genetic testing, and the results were available at tafamidis start for 1208 (62.2%) patients: 995 (82.4%) had wild-type ATTR and 213 (17.6%) had hereditary ATTR. Most patients started treatment≤12months after diagnosis (88.3%): 2268 (81.3%) at 20mg/day, with 401 (17.7%) increasing to 80mg/day. Median follow-up duration was 11.8months. New York Heart Association class improved or remained stable for 1299 (77.6%), whereas 376 (22.4%) worsened between inclusion and last follow-up. Among patients initiated at 80mg, 297 (81.1%) improved or remained stable and 69 (18.9%) worsened. New York Heart Association class progression did not vary with age. The 18-month survival rates were 89.8% (95% confidence interval: 87.0–92.0) among patients aged<80years, and 86.5% (95% confidence interval: 83.9–88.7) among those aged≥80years. ConclusionsEarly tafamidis meglumine access was given to 2788 patients with ATTR-CM. New York Heart Association class progression and survival were consistent with previously published data.

A Snapshot of the Most Recent Transthyretin Stabilizers.

In recent years, several strategies have been developed for the treatment of transthyretin-related amyloidosis, whose complex clinical manifestations involve cardiomyopathy and polyneuropathy. In view of this, transthyretin stabilizers represent a major cornerstone in treatment thanks to the introduction of tafamidis into therapy and the entry of acoramidis into clinical trials. However, the clinical treatment of transthyretin-related amyloidosis still presents several challenges, urging the development of new and improved therapeutics. Bearing this in mind, in this paper, the most promising among the recently published transthyretin stabilizers were reviewed. Their activity was described to provide some insights into their clinical potential, and crystallographic data were provided to explain their modes of action. Finally, structure-activity relationship studies were performed to give some guidance to future researchers aiming to synthesize new transthyretin stabilizers. Interestingly, some new details emerged with respect to the previously known general rules that guided the design of new compounds.

Cochlear implants for hereditary ATTR amyloidosis: a case report of two cases.

To analyze the clinical presentation, management, and outcome of two sisters affected by hereditary transthyretin related amyloidosis (ATTRv) and bilateral severe-to-profound hearing loss treated with cochlear implant. A description of two patients underwent three cochlear implant (CI) surgery was performed. Age at time of implantation ranged from 48 to 53years. Both patients were initially equipped with a bilateral hearing aid and subsequently underwent cochlear implant. A bimodal stimulation was maintained thereafter. One case underwent bilateral surgery. Hearing outcomes were assessed by comparing pre- and post-operatively tonal and vocal hearing thresholds and speech perception tests (Common Evaluation Protocol Results in Rehabilitation Audiology). In both patients, a significant and stable improvement of hearing threshold and speech perception was observed up to the last follow-up. No post-operative complication were observed during the follow-up. ATTRv amyloidosis may be the cause of cochlear function impairment. Restoring the hearing in these group of patients is of paramount importance since the vision is often compromised too. Cochlear implant could be a viable strategy of rehabilitation for selected patients affected by severe-to-profound sensorineural hearing loss caused by ATTRv amyloidosis.

Transthyretin monomers: a new plasma biomarker for pre-symptomatic transthyretin-related amyloidosis

Background Genotyping and amyloid fibril detection in tissues are generally considered the diagnostic gold standard in transthyretin-related amyloidosis. Patients carry less stable TTR homotetramers prone to dissociation into non-native monomers, which rapidly self-assemble into oligomers and, ultimately, amyloid fibrils. Thus, the initial event of the amyloid cascade produces the smallest transthyretin species: the monomers. This creates engineering opportunities for diagnosis that remain unexplored. Methods We hypothesise that molecular sieving represents a promising method for isolating and concentrating trace TTR monomers from the tetramers present in plasma samples. Subsequently, immunodetection can be utilised to distinguish monomeric TTR from other low molecular weight proteins within the adsorbed fraction. A two-step assay was devised (ImmunoSieve assay), combining molecular sieving and immunodetection for sensing monomeric transthyretin. This assay was employed to analyse plasma microsamples from 10 individuals, including 5 pre-symptomatic carriers of TTR-V30M, the most prevalent amyloidosis-associated TTR variant worldwide, and 5 healthy controls. Results The ImmunoSieve assay enable sensitive detection of monomeric transthyretin in plasma microsamples. Moreover, the circulating monomeric TTR levels were significantly higher in carriers of amyloidogenic TTR mutation. Conclusions Monomeric TTR can function as a biomarker for evaluating disease progression and assessing responses to therapies targeted at stabilising native TTR.

Parametric mapping using cardiovascular magnetic resonance for the differentiation of light chain amyloidosis and transthyretin-related amyloidosis.

To evaluate different cardiovascular magnetic resonance (CMR) parameters for the differentiation of light chain amyloidosis (AL) and transthyretin-related amyloidosis (ATTR). In total, 75 patients, 53 with cardiac amyloidosis (20 patients with AL (66±12 years, 14 males [70%]) and 33 patients with ATTR (78±5 years, 28 males [88%])) were retrospectively analyzed regarding CMR parameters such as T1 and T2 mapping, extracellular volume (ECV), and late gadolinium enhancement (LGE) distribution patterns, and myocardial strain, and compared to a control cohort with other causes of left ventricular hypertrophy (LVH; 22 patients (53±16 years, 17 males [85%])). One way-ANOVA and receiver operating characteristic analysis were used for statistical analysis. ECV was the single best parameter to differentiate between cardiac amyloidosis and controls (area under the curve [AUC]: 0.97, 95% confidence intervals [CI]: 0.89-0.99, p<.0001, cutoff: >30%). T2 mapping was the best single parameter to differentiate between AL and ATTR amyloidosis (AL: 63±4 ms, ATTR: 58±2 ms, p<.001, AUC: 0.86, 95% CI: 0.74-0.94, cutoff: >61 ms). Subendocardial LGE was predominantly observed in AL patients (10/20 [50%] vs. 5/33 [15%]; p=.002). Transmural LGE was predominantly observed in ATTR patients (23/33 [70%] vs. 2/20 [10%]; p<.001). The diagnostic performance of T2 mapping to differentiate between AL and ATTR amyloidosis was further increased with the inclusion of LGE patterns (AUC: 0.96, 95% CI: 0.86-0.99]; p=.05). ECV differentiates cardiac amyloidosis from other causes of LVH. T2 mapping combined with LGE differentiates AL from ATTR amyloidosis with high accuracy on a patient level.

Islands and Neurology: An Exploration into a Unique Association.

The current study investigates the intricate connection between neurology and islands shedding light on the historical, epidemiological, and genetic aspects. Based on an elaborate literature review, we identified neurological conditions having a significant clustering in an island(s), confined to a particular island(s), named after an island, and described first in an island. The genetic factors played a crucial role, uncovering disorders like Cayman ataxia, Machado Joseph disease, SGCE-mediated dystonia-myoclonus syndrome, X-linked dystonia parkinsonism, hereditary transthyretinrelated amyloidosis, Charcot Marie Tooth 4F, and progressive myoclonic epilepsy syndromes, that exhibited remarkable clustering in diverse islands. Local customs also left enduring imprints. Practices such as cannibalism in Papua New Guinea led to Kuru, while cycad seed consumption in Guam triggered Lytico-Bodig disease. Toxin-mediated neurologic disorders exhibited intricate island connections, exemplified by Minamata disease in Kyushu islands and atypical parkinsonism in French Caribbean islands. Additionally, the Cuban epidemic of amblyopia and neuropathy was associated with severe nutritional deficiencies. This study pioneers a comprehensive review narrating the genetic, environmental, and cultural factors highlighting the spectrum of neurological disorders in island settings. It enriches the medical literature with a unique understanding of the diverse influences shaping neurological health in island environments.

Value of multi-modality small fiber assessments in a genotypically diverse cohort of transthyretin-related amyloidosis in the early stages of disease

IntroductionTransthyretin-related amyloidosis (ATTRv) is a progressive multisystem disorder, predominantly involving the peripheral nerve system (PNS) and heart. Quantification of small fiber damage may help guide treatment decisions, as amyloid deposits frequently affect those fibers early in disease course. Corneal confocal microscopy (CCM) is a promising method to monitor patients with ATTRv, due to similarities between corneal nerves and PNS, as the cornea is innervated by Aδ and C fibers. MethodsWe compared CCM measures from ATTRv patients to a group of healthy individuals, matched by age and gender. We then investigated the correlations between small fiber tests (SFT): CCM, LDI-Flare and CDT, COMPASS-31 and disability scales (RODS and ONLS) in patients. ResultsOf 20 patients (6 with V30M), mean age 50.3±15.3Y, 7 female (35%), six (30%) had polyneuropathy and 10 (50%) carpal tunnel syndrome. CDT was abnormal in 9 and LDI-flare in 6 patients. CCM was abnormal in 19 tested patients and significantly reduced when compared to controls (CNFL: 6.31±0.31 vs. 15.21±1.02mm/mm2, p<0.001). Mean COMPASS-31-scores were 22.27±22.84; RODS and ONLS were 38.15±12.33 and 2.05±2.3, with no significant differences between sub-group scores. Disease duration was significantly correlated with ONLS (0.43, p=0.05) and RODS (0.46, p=0.03). There were no significant correlations between measures of disability and SFT. ConclusionsIn a diverse cohort of ATTRv patients, CCM was the most frequent abnormal measurement. CCM can be a useful test to triage patients in the early disease stages and with few or equivocal symptoms.

Genetic counselling for at-risk family members with hereditary transthyretin amyloidosis: data from a single-centre study

Background Hereditary transthyretin-related amyloidosis is an autosomal dominant disorder. Recently, disease-modifying therapies (DMTs) have been developed. For at-risk individuals, genetic analysis aids in the early administration of medical care; however, few studies have evaluated the current status of genetic counselling and management of presymptomatic carriers of amyloidogenic variants. Methods We retrospectively evaluated the medical records of 202 consecutive participants. Results A total of 103 clients who received genetic counselling for predictive testing were at-risk, and 83 underwent predictive testing. Genetic testing results were positive in 33 patients, 11 of whom had confirmed amyloid deposition and were administered DMTs. For presymptomatic V30M (p.V50M) carriers, 32.0 ± 2.4 years (median ± standard error) was the age when amyloid deposition was first identified (95% confidence interval 27.4–36.6). Serum transthyretin (TTR) levels decreased serially with an estimated slope of −1.2 mg/dL/year. Conclusions Our study suggests the clinical utility of management using a combination of predictive testing and monitoring methods. Psychosocial support should be considered with collaboration between geneticists/genetic counsellors and psychologists. For a more optimised protocol for monitoring and designing future interventional trials in presymptomatic carriers, prospective cohort studies are necessary to clarify the natural history, particularly in the early stages of the disease.

Reproducibility of the quantitative assessment of myocardial 99mTc-labeled diphosphonate uptake in patients with suspected transthyretin-related cardiac amyloidosis: A test-retest study

Reproducibility of the quantitative assessment of myocardial 99mTc-labeled diphosphonate uptake in patients with suspected transthyretin-related cardiac amyloidosis: A test-retest study

Cardiac DPD-uptake time dependency in ATTR patients verified by quantitative SPECT/CT and semiquantitative planar parameters

BackgroundBone scintigraphy plays an important role in the diagnosis of cardiac Transthyretin-Related Amyloidosis (ATTR). The mechanism of myocardial tracer accumulation and its dependence over time are not fully understood. Recently, a scintigraphic quantification of the cardiac amyloid deposition has been discussed. Nevertheless, little is known regarding the right time of quantitative imaging. MethodsThe geometrical mean of decay corrected total counts over the heart and the heart/whole-body ratio (H/WB) were evaluated in 23 patients undergoing DPD-bone scan with planar whole-body images 1 and 3 hours post injection (p.i.). Myocardial standard uptake values (SUV)peak were assessed in another 15 patients with quantitative SPECT/CT imaging 1 hours and 3 hours p.i.. ResultsTotal counts over the heart (1 hours p.i.: 81,676 cts, range 69,887 to 93,091 cts and 3 hours p.i.: 64,819 cts, range 52,048 to 86,123 cts, P = .0005) and H/WB ratio (1 hours p.i.:0.076 ± 0.020 and 3 hours p.i. 0.070 ± 0.022; P = .0003) were significantly increased 1 hours p.i.. Furthermore median myocardial SUVpeak (1 hours p.i.:12.2, range 9.6 to 18.9 and 3 hours p.i.: 9.6, range 8.2 to 15.0, P = 0.0012) was also significantly higher after 1 hours p.i. compared to 3 hours p.i.. ConclusionCardiac DPD activity and myocardial SUVpeak are time-dependent, which should be considered when using quantitative bone scintigraphy in ATTR patients.

Role of Imaging in Cardiomyopathies.

Imaging has a central role in the diagnosis, classification, and clinical management of cardiomyopathies. While echocardiography is the first-line technique, given its wide availability and safety, advanced imaging, including cardiovascular magnetic resonance (CMR), nuclear medicine and CT, is increasingly needed to refine the diagnosis or guide therapeutic decision-making. In selected cases, such as in transthyretin-related cardiac amyloidosis or in arrhythmogenic cardiomyopathy, the demonstration of histological features of the disease can be avoided when typical findings are observed at bone-tracer scintigraphy or CMR, respectively. Findings from imaging techniques should always be integrated with data from the clinical, electrocardiographic, biomarker, genetic and functional evaluation to pursue an individualised approach to patients with cardiomyopathy.

5-Nitro-1,2-benzothiazol-3-amine and N-Ethyl-1-[(ethylcarbamoyl)(5-nitro-1,2-benzothiazol-3-yl)amino]formamide Modulate α-Synuclein and Tau Aggregation.

Protein misfolding results in a plethora of known diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, transthyretin-related amyloidosis, type 2 diabetes, Lewy body dementia, and spongiform encephalopathy. To provide a diverse portfolio of therapeutic small molecules with the ability to reduce protein misfolding, we evaluated a set of 13 compounds: 4-(benzo[d]thiazol-2-yl)aniline (BTA) and its derivatives containing urea (1), thiourea (2), sulfonamide (3), triazole (4), and triazine (5) linker. In addition, we explored small modifications on a very potent antioligomer 5-nitro-1,2-benzothiazol-3-amine (5-NBA) (compounds 6-13). This study aims to define the activity of BTA and its derivatives on a variety of prone-to-aggregate proteins such as transthyretin (TTR81-127, TTR101-125), α-synuclein (α-syn), and tau isoform 2N4R (tau 2N4R) through various biophysical methods. Thioflavin T (ThT) fluorescence assay was used to monitor fibril formation of the previously mentioned proteins after treatment with BTA and its derivatives. Antifibrillary activity was confirmed using transmission electron microscopy (TEM). Photoreactive cross-linking assay (PICUP) was utilized to detect antioligomer activity and lead to the identification of 5-NBA (at low micromolar concentration) and compound 13 (at high concentration) as the most promising in reducing oligomerization. 5-NBA and not BTA inhibited the inclusion formation based on the cell-based assay using M17D neuroblastoma cells that express inclusion-prone αS-3K::YFP. 5-NBA abrogated the fibril, oligomer, and inclusion formation in a dose-dependent manner. 5-NBA derivatives could be the key to mitigate protein aggregation. In the future, the results made from this study will provide an initial platform to generate more potent inhibitors of α-syn and tau 2N4R oligomer and fibril formation.

New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2022.

Cardiovascular diseases (CVD) remain the leading cause of death worldwide and pharmacotherapy of most of them is suboptimal. Thus, there is a clear unmet clinical need to develop new pharmacological strategies with greater efficacy and better safety profiles. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2022 including the approval of first-in-class drugs that open new avenues for the treatment of obstructive hypertrophic cardiomyopathy (mavacamten), type 2 diabetes mellitus (tirzepatide), and heart failure (HF) independent of left ventricular ejection fraction (sodium-glucose cotransporter 2 inhibitors). We also dealt with fixed dose combination therapies repurposing different formulations of "old" drugs with well-known efficacy and safety for the treatment of patients with acute decompensated HF (acetazolamide plus loop diuretics), atherosclerotic cardiovascular disease (moderate-dose statin plus ezetimibe), Marfan syndrome (angiotensin receptor blockers plus β-blockers), and secondary cardiovascular prevention (i.e. low-dose aspirin, ramipril and atorvastatin), thereby filling existing gaps in knowledge, and opening new avenues for the treatment of CVD. Clinical trials confirming the role of dapagliflozin in patients with HF and mildly reduced or preserved ejection fraction, long-term evolocumab to reduce the risk of cardiovascular events, vitamin K antagonists for stroke prevention in patients with rheumatic heart disease-associated atrial fibrillation, antibiotic prophylaxis in patients at high risk for infective endocarditis before invasive dental procedures, and vutrisiran for the treatment of hereditary transthyretin-related amyloidosis with polyneuropathy were also reviewed. Finally, we briefly discuss recent clinical trials suggesting that FXIa inhibitors may have the potential to uncouple thrombosis from hemostasis and attenuate/prevent thromboembolic events with minimal disruption of hemostasis.

Prevalence of transthyretin-related amyloidosis in Tuscany: Data from the regional population-based registry

The limited available data regarding the prevalence of transthyretin amyloidosis, both for wild-type (ATTRwt) and hereditary form (ATTRv), is inferred from highly selected patients and subsequent extrapolations that limit the comprehension of the clinical disease impact. The Tuscan healthcare system in 2006 developed a web-based rare disease registry, to monitor and profile patients affected by rare diseases.Clinicians belonging to regional validated healthcare data centres can register patients at the diagnosis, with a rigorous approach and distinguishing the types of amyloidosis, i.e., ATTRwt versus ATTRv. Thanks to this data collection method, available from July 2006 and extended with electronic therapy plans related to a diagnosis since May 2017, we analysed prevalence and incidence of ATTR and its subtypes. On November 30th 2022, ATTRwt prevalence in Tuscany is 90.3 per 1,000,000 persons and ATTRv prevalence is 9.5 per 1,000,000 persons, whereas the annual incidence ranges from 14.4 to 26.7 per 1,000,000 persons and from 0.8 to 2.7 per 1,000,000 persons, respectively. The male gender is predominant in both forms. All except one patient showed evidence of cardiomyopathy. This epidemiological data requires attention, not only to increase the effort for the clinical management and earlier diagnosis, but also to underline the need for the disease-specific treatments.

Risk stratification in transthyretin-related cardiac amyloidosis.

Transthyretin related cardiac amyloidosis (TTR-CA) is an infiltrative cardiomyopathy that cause heart failure with preserved ejection fraction, mainly in aging people. Due to the introduction of a non invasive diagnostic algorithm, this disease, previously considered to be rare, is increasingly recognized. The natural history of TTR-CA includes two different stages: a presymptomatic and a symptomatic stage. Due to the availability of new disease-modifying therapies, the need to reach a diagnosis in the first stage has become impelling. While in variant TTR-CA an early identification of the disease may be obtained with a genetic screening in proband's relatives, in the wild-type form it represents a challenging issue. Once the diagnosis has been made, in order to identifying patients with a higher risk of cardiovascular events and death it is necessary to focus on risk stratification. Two prognostic scores have been proposed both based on biomarkers and laboratory findings. However, a multiparametric approach combining information from electrocardiogram, echocardiogram, cardiopulmonary exercise test and cardiac magnetic resonance may be warranted for a more comprehensive risk prediction. In this review, we aim at evaluating a step by step risk stratification, providing a clinical diagnostic and prognostic approach for the management of patients with TTR-CA.

Multimodality imaging in the diagnostic management of concomitant aortic stenosis and transthyretin-related wild-type cardiac amyloidosis.

Severe aortic stenosis (AS) is the most common valvular heart disease with a prevalence rate of more than 4% in 75-year-old people or older. Similarly, cardiac amyloidosis (CA), especially "wild-type transthyretin" (wTTR), has shown a prevalence rate ranging from 22% to 25% in people older than 80 years. The detection of the concomitant presence of CA and AS is challenging primarily because of the similar type of changes in the left ventricle caused by AS and CA, which share some morphological characteristics. The aim of this review is to identify the imaging triggers in order to recognize occult wtATTR-CA in patients with AS, clarifying the crucial step of the diagnostic process. Multimodality imaging methods such as echocardiography, cardiac magnetic resonance, cardiac computed tomography, and DPD scintigraphy will be analyzed as part of the available diagnostic workup to identify wtATTR-CA early in patients with AS.

CMR-based right ventricular strain analysis in cardiac amyloidosis and its potential as a supportive diagnostic feature.

Right ventricular (RV) strain has provided valuable prognostic information for patients with cardiac amyloidosis (CA). However, the extent to which RV strain and strain rate can differentiate CA is not yet clinically established. CA underdiagnosis delays treatment strategies and exacerbates patient prognosis. Evaluation of cardiac magnetic resonance (CMR) quantified RV global and regional strain of CA and HCM patients along with CA subtypes. CMR feature tracking attained longitudinal, radial and circumferential global and regional strain in 47 control subjects (CTRL), 43 CA-, 20 hypertrophic cardiomyopathy- (HCM) patients. CA patients were subdivided in 21 transthyretin-related amyloidosis (ATTR) and 20 acquired immunoglobulin light chain (AL) patients. Strain data and baseline clinical parameters were statistically analysed with respect to diagnostic performance and discriminatory power between the different clinical entities. Effective differentiation of CA from HCM patients was achieved utilizing global longitudinal (GLS: 16.5±3.9% vs. -21.3±6.7%, p=0.032), radial (GRS: 11.7±5.3% vs. 16.5±7.1%, p<0.001) and circumferential (GCS: -7.6±4.0% vs. -9.4±4.4%, p=0.015) right ventricular strain. Highest strain-based hypertrophic phenotype differentiation was attained using GRS (AUC=0.86). Binomial regression found right ventricular ejection fraction (RV-EF) (p=0.017) to be a significant predictor of CA-HCM differentiation. CA subtypes had comparable cardiac strains. CMR-derived RV global strains and various regional longitudinal strains provide discriminative radiological features for CA-HCM differentiation. However, in terms of feasibility, cine-derived RV-EF quantification may suffice for efficient differential diagnostic support.