Can Nuclear Imaging Techniques Predict Patient Outcome and Guide Medical Management in Hereditary Transthyretin Cardiac Amyloidosis?

International audiencePurpose of Review Nuclear imaging recently gained a key role in the diagnosis and prognostic assessment of transthyretin (TTR)-related cardiac amyloidosis. This review aims at summarizing the state-of-the art regarding the implementation of nuclear imaging in the management of hereditary mutated TTR-cardiac amyloidosis (mTTR-CA). Recent Findings Although cardiac uptake of bone tracers is acknowledged as a specific marker of TTR amyloid cardiac burden, recent studies validated the implementation of bone scan in the flow chart for non-invasive diagnosis and follow-up of CA in multicenter trials. Simultaneously, cardiac denervation evidenced by MIBG scintigraphy proved to be a strong and independent prognostic marker of poor outcome in mTTR-CA. Summary By its unique ability to assess both amyloid burden and cardiac denervation, nuclear imaging may prove useful as part of multimodality imaging tools to trigger treatment initiation and monitoring in patients with mTTR-CA

Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by Diphosphonates scintigraphy in patients with aTTR-FAP

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Cardiac denervation evidenced by MIBG occurs earlier than amyloid deposits detection by Diphosphonates scintigraphy in patients with aTTR-FAP

International audienc

Multi-modality imaging in cardiac ATTR familial amyloidosis: agreement between echocardiography, MRI and DPD-scintigraphy

From First European Congress on Hereditary ATTR amyloidosisParis, France. 2-3 November 2015International audienceBackgroundThree main imaging techniques are commonly used to identify cardiac transthyretin (ATTR) amyloidosis: echocardiography, MRI and DPD scintigraphy. Each one provides specific diagnostic and prognostic informations but also has its specific limitations. We sought to evaluate a multimodality imaging strategy to diagnose cardiac amyloidosis in ATTR.MethodsSeventy seven consecutive patients with multimodality imaging evaluation (echocardiography, 1.5T MRI and 99mTc-DPD scintigraphy) to diagnose cardiac amyloidosis were identified from the database of the French National Reference Center for Amyloidosis. Patients with pacemaker or severe renal failure did not undergo cardiac MRI and were analyzed on the basis of the echocardiography and scintigraphy (n=17). Three groups were compared: patients with positive agreement to diagnose cardiac ATTR (PA-ATTR group), patients with positive agreement to exclude cardiac ATTR (PA-normal) and patients with negative agreement (NA).ResultsThe mean age was 52 years [44-70]; 59% were male. Transthyretin mutations were Val30Met in 67%, other in 21%, and 12% had acquired ATTR from previous domino liver transplantation; 30 patients had a positive echocardiography, 37 positive MRI and 36 positive DPD scintigraphy. Positive imaging agreement was encountered in 50/77 patients (65%: 30 PA-ATTR and 20 PA-normal). Negative agreement was observed in 27/77 patients (35%). Compared with PA-ATTR patients, NA patients were younger (68 [64-72] years vs. 46 [41-64], had lower BNP levels (149 [94-248] pg/ml vs. 40 [25-102],) and thinner interventricular septum (17 [14-20] mm vs. 12 [10-14]), all p values <0.0001). The two main causes for negative agreement between techniques was the sole positivity of the MRI (n=10) and the sole negativity of the DPD scintigraphy(n=6). Compared with PA-ATTR patients, patients with a sole MRI positivity were younger (41 [39-44] years vs. 68 [64-72] p<0.001), more frequently women (80% vs.26% p=0,002), had thinner interventricular septum (9 [8-11] mm vs.17 [14-20], p<0.0001), had lower BNP levels (26 [24-36] vs 149 [92-249] p<0.0001) and had less diffuse late gadolinium enhancement pattern (10% vs. 66% patients; p<0.0001). As compared with PA-ATTR patients, patients with a sole negativity of the DPD scintigraphy had acquired ATTR from domino liver transplantation in all but one case (83% vs. 6% patients; p=0.02).ConclusionsIn transthyretin amyloidosis, the agreement between echocardiography, cardiac MRI and DPD scintigraphy to diagnose cardiac amyloidosis was observed in 65% of patients. Patients without agreement between these three techniques had distinct patterns of cardiac involvement: sole positivity of the MRI was encountered in patients in the early stages of ATTR; patients with acquired ATTR due to domino liver transplantation often had negative DPD scintigraphy

Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability

International audienceMarfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying FBN1 mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the “Carter effect” in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity

Cardiac Dysautonomia Predicts Long-Term Survival in Hereditary Transthyretin Amyloidosis After Liver Transplantation

International audienceOBJECTIVES This study sought to compare techniques evaluating cardiac dysautonomia and predicting the risk of death of patients with hereditary transthyretin amyloidosis (mATTR) after liver transplantation (LT). BACKGROUND mATTR is a multisystemic disease involving mainly the heart and the peripheral nervous system. LT is the reference treatment, and pre-operative detection of high-risk patients is critical. Cardiovascular dysautonomia is commonly encountered in ATTR and may affect patient outcome, although it is not known yet which technique should be used in the field to evaluate it. METHODS In a series of 215 consecutive mATTR patients who underwent LT, cardiac dysautonomia was assessed by a dedicated clinical score, time-domain heart rate variability, (123)-meta-iodobenzylguanidine heart/mediastinum ((123)-MIBG H/M) ratio on scintigraphy, and heart rate response to atropine (HRRA). RESULTS Patient median age was 43 years, 62% were male and 69% carried the Val30Met mutation. Cardiac dysautonomia was documented by at least 1 technique for all patients but 6 (97%). In univariate analysis, clinical score, (123)-MIBG H/M ratio and HRRA were associated with mortality but not heart rate variability. The (123)-MIBG H/M ratio and HRRA had greater area under the curve (AUC) of receiver-operating characteristic curves than clinical score and heart rate variability (AUC: 0.787, 0.748, 0.656, and 0.523, respectively). Multivariate score models were then built using the following variables: New York Heart Association functional class, interventricular septum thickness, and either (123)-MIBG H/M ratio (SMIBG) or HRRA (S-atropine). AUC of S-MIBG and S-atropine were greater than AUC of univariate models, although nonsignificantly (AUC: 0.798 and 0.799, respectively). Predictive powers of S-MIBG, S-atropine, and a reference clinical model (AUC: 0.785) were similar. CONCLUSIONS Evaluation of cardiac dysautonomia is a valuable addition for predicting survival of mATTR patients following LT. Among the different techniques that evaluate cardiac dysautonomia, (123)-MIBG scintigraphy and heart rate response to atropine had better prognostic accuracy. Multivariate models did not improve significantly prediction of outcome. (C) 2016 by the American College of Cardiology Foundation

Clinical relevance of genotype–phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants

International audiencePurpose: Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 gene, few genotype-phenotype correlations have been found in proband studies only.Methods: In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations.Results: A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants.Conclusion: This study shows that FBN1 genotype-phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs