Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy

Background: The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome. Methods: Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality. Results: Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; P<0.001), whereas Perugini grade was not associated with survival (P=0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; P<0.001), presence of the p.(V142I) TTR variant (HR, 1.42 [95% CI, 1.20-1.81]; P=0.004), National Amyloidosis Centre stage (each category, P<0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; P=0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; P=0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; P=0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; P<0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; P<0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM (P<0.001 and P=0.02, respectively). Conclusions: Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis

Early diagnosis, disease stage and prognosis in wild‐type transthyretin amyloid cardiomyopathy: The DIAMOND study

Aims: Disease staging and prognostic scoring in wild-type transthyretin-related cardiac amyloidosis (ATTRwt-CA) can be captured by two systems (NAC and Columbia scores). However, uncertainty remains as epidemiology of the disease is evolving rapidly. We evaluated features associated with staging systems across ATTRwt-CA patients from different diagnostic pathways, and their association with prognosis. Methods: We performed an analysis on DIAMOND patients with available data to evaluate NAC and Columbia score. DIAMOND was a retrospective study from 17 Italian referral centres for CA, enrolling 1281 patients diagnosed between 2016 and 2021, and aimed at describing characteristics of pathways leading to ATTRwt-CA diagnosis. Of the original cohort, 811 patients were included in this analysis. Each patient had NAC and Columbia score calculated. Patients were grouped according to NAC and Columbia scoring classes. We described characteristics of patients according to staging classes and diagnostic pathways at diagnosis. Prevalence of early diagnoses, defined as NAC Ia, NYHA class I, no use of diuretics, no history of heart failure (HF) hospitalizations nor of atrial fibrillation prior to diagnosis, was investigated. Finally, prognostic variables were tested alone and grouped as NAC or Columbia scores in Cox univariate and multivariate regression analyses. Prognosis was investigated as all-cause mortality, in the whole population and dividing patients in HF versus other diagnostic pathways. Results: Only 1% of the study population had an early ATTRwt-CA diagnosis. Distribution of prognostic variables and of NAC and Columbia classes was heterogeneous across diagnostic pathways. The prevalence of NAC III and Columbia III was higher in the HF diagnostic pathway, but all NAC and Columbia classes were present in all pathways. Both NAC and Columbia scores were associated with all-cause mortality at univariate Cox regression analysis in the whole population, in patients from the HF diagnostic pathway and in those from other pathways. At multivariate analysis, Columbia score remained significantly associated with the outcome, together with age at diagnosis, left ventricular ejection fraction and maximal wall thickness. Conclusions: In this contemporary nationwide cohort, an ATTRwt-CA early diagnosis was very rare. Disease staging with NAC and Columbia scoring systems determined classes of patients with heterogeneous features. Both scores were significantly associated with mortality, but other variables also had prognostic significance

Conceptual Design of a Soft X‐ray SASE‐FEL Source

FELs based on SASE are believed to be powerful tools to explore the frontiers of basic sciences, from physics to chemistry to biology. Intense R&D programs have started in the USA and Europe in order to understand the SASE physics and to prove the feasibility of these sources. The allocation of considerable resources in the Italian National Research Plan (PNR) brought about the formation of a CNR‐ENEA‐INFN‐University of Roma "Tor Vergata" study group. A conceptual design study has been developed and possible schemes for linac sources have been investigated, bringing to the SPARX proposal. We report in this paper the results of a preliminary start to end simulation concerning one option we are considering based on an S‐band normal conducting linac with high brightness photoinjector integrated in a RF compressor

Human population genomics of the Western Mediterranean

This work explores the genetic landscape of the Western Mediterranean basin. Genome-wide data have been used in order to describe the genetics of the Island of Ibiza and France. In the first case, we found Ibiza being isolated from the other Spanish groups and linked this finding to genetic drift and inbreeding, also excluding any connection with the ancient Phoenician colonists often identified as direct ancestors of the islanders. Regarding France, we used sophisticated haplotype-based methods to disentangle the genetic landscape of this understudied European country and presented the first genetic picture of this population.Este trabajo explora el panorama genético presente en la cuenca del Mediterráneo Occidental. Se han utilizado datos de todo el genoma para describir la genética de la isla de Ibiza y Francia. En el primer caso, encontramos a Ibiza asilada del resto de grupos españoles y relacionamos este descubrimiento con el efecto de la deriva génica y la endogamia, excluyendo también cualquier conexión con los antiguos colonos Fenicios habitualmente identificados como ancestros directos de los isleños. Con respecto a Francia, usamos métodos sofisticados basados en haplotipos para describir el paisaje genético de este país europeo poco estudiado hasta la fecha, presentando la primera imagen genética de su población

Human population genomics of the Western Mediterranean

This work explores the genetic landscape of the Western Mediterranean basin. Genome-wide data have been used in order to describe the genetics of the Island of Ibiza and France. In the first case, we found Ibiza being isolated from the other Spanish groups and linked this finding to genetic drift and inbreeding, also excluding any connection with the ancient Phoenician colonists often identified as direct ancestors of the islanders. Regarding France, we used sophisticated haplotype-based methods to disentangle the genetic landscape of this understudied European country and presented the first genetic picture of this population.Este trabajo explora el panorama genético presente en la cuenca del Mediterráneo Occidental. Se han utilizado datos de todo el genoma para describir la genética de la isla de Ibiza y Francia. En el primer caso, encontramos a Ibiza asilada del resto de grupos españoles y relacionamos este descubrimiento con el efecto de la deriva génica y la endogamia, excluyendo también cualquier conexión con los antiguos colonos Fenicios habitualmente identificados como ancestros directos de los isleños. Con respecto a Francia, usamos métodos sofisticados basados en haplotipos para describir el paisaje genético de este país europeo poco estudiado hasta la fecha, presentando la primera imagen genética de su población

Reshaping the Hexagone: the genetic landscape of modern France

Poster presented at the Human Evolution, held between 30th Octuber and 1st November in 2019, in Cambridge (UK).Unlike other European countries, Metropolitan France is surprisingly understudied. We have combined newly genotyped samples from various zones in France with publicly available data and applied both allele frequency and haplotype-based methods in order to describe the internal structure of this country, taking advantage of the Human Origins SNP array, specifically designed for human population genetics studies. We found out that French Basques are genetically distinct from all other populations in the Hexagone and that the populations from southwest France (namely the Franco-Cantabrian region) are intermediate between Basques and other populations. Moreover, Bretons slightly separated from the rest of the groups and a link with the historical gene flow from the British Isles has been found. Results from the allele frequency analyses point to a general background that appears to be a mixture of two components, one closer to Southern Italy and the other to Ireland. This combination may be the result of a contact that happened in two different moments: in the Early Neolithic, and then Ireland would be a proxy for the continental pathway for the Neolithic wave of advance and South Italy for the coastal penetration, or the Iron Age, when the Celtic and the Mediterranean worlds met in France. On the other hand, results from the haplotype-based methods describe a more structured landscape, highlighting the presence of areas characterized by differential links with the neighboring populations, possibly reflecting a more recent history

Reshaping the Hexagone: the genetic landscape of modern France

Poster presented at the Human Evolution, held between 30th Octuber and 1st November in 2019, in Cambridge (UK).Unlike other European countries, Metropolitan France is surprisingly understudied. We have combined newly genotyped samples from various zones in France with publicly available data and applied both allele frequency and haplotype-based methods in order to describe the internal structure of this country, taking advantage of the Human Origins SNP array, specifically designed for human population genetics studies. We found out that French Basques are genetically distinct from all other populations in the Hexagone and that the populations from southwest France (namely the Franco-Cantabrian region) are intermediate between Basques and other populations. Moreover, Bretons slightly separated from the rest of the groups and a link with the historical gene flow from the British Isles has been found. Results from the allele frequency analyses point to a general background that appears to be a mixture of two components, one closer to Southern Italy and the other to Ireland. This combination may be the result of a contact that happened in two different moments: in the Early Neolithic, and then Ireland would be a proxy for the continental pathway for the Neolithic wave of advance and South Italy for the coastal penetration, or the Iron Age, when the Celtic and the Mediterranean worlds met in France. On the other hand, results from the haplotype-based methods describe a more structured landscape, highlighting the presence of areas characterized by differential links with the neighboring populations, possibly reflecting a more recent history