Publications by authors named "Violaine Plante-Bordeneuve"

64 Publications

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study.

Lancet Neurol 2021 01 16;20(1):49-59. Epub 2020 Nov 16.

Centro Hospitalar Universitário do Porto, Porto, Portugal.

Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261.

Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups.

Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Funding: Alnylam Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(20)30368-9DOI Listing
January 2021

New data on the genetic profile and penetrance of hereditary Val30Met transthyretin amyloidosis in Sweden.

Amyloid 2020 Nov 4:1-7. Epub 2020 Nov 4.

Department of Neurology, Henri Mondor University Hospital, APHP, Créteil, France.

Introduction: Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease's risk, we performed a comprehensive study of ATTRV30M families in Sweden.

Methods: To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates' effect on the disease's risk.

Results: We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 [Standard Deviation (SD) =10.03] years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years,  < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% [95% confidence interval (CI) = 6-10] at 40 years-old, increasing to 71% [95% CI= 65-76] at age 90 years. The risk was found to be higher in male patients ( < .01) and in case of maternal transmission ( < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals.

Conclusions: Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.
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http://dx.doi.org/10.1080/13506129.2020.1841623DOI Listing
November 2020

Natural history and impact of treatment with tafamidis on major cardiovascular outcome-free survival time in a cohort of patients with transthyretin amyloidosis.

Eur J Heart Fail 2021 Feb 9;23(2):264-274. Epub 2020 Nov 9.

AP-HP (Assistance Publique-Hôpitaux de Paris), Cardiology Department, DHU-ATVB, Henri Mondor University Hospital, Créteil, France.

Aims: Hereditary (ATTRv) and wild-type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR-ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real-life population in comparison to the population included in the ATTR-ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)-free survival time without cardiac decompensation, heart transplant, or death.

Methods And Results: From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR-ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO-free survival time (n = 98): 1565 (1010-2400) days vs. 771 (686-895) days without treatment (log-rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N-terminal pro-B-type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P = 0.0132).

Conclusion: In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR-ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real-life population.
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http://dx.doi.org/10.1002/ejhf.2028DOI Listing
February 2021

Strategies to improve the quality of life in patients with hereditary transthyretin amyloidosis (hATTR) and autonomic neuropathy.

Clin Auton Res 2019 09 10;29(Suppl 1):25-31. Epub 2019 Sep 10.

Department of Neurology, Henri Mondor University Hospital, 51 avenue de Lattre de Tassigny, 94010, Creteil Cedex, France.

Purpose: Hereditary transthyretin amyloidosis (hATTR) is a severe adult-onset progressive disease mainly involving the peripheral nervous system and the heart, with a prominent impact on the autonomic nervous system. This review summarizes the clinical aspects of autonomic dysfunction in hATTR, and their impact on quality of life as well as potential therapeutic options.

Methods: Literature review.

Results: Autonomic dysfunction, causing neurogenic orthostatic hypotension, gastroparesis, constipation, diarrhea, bladder dysfunction, and erectile dysfunction in males, has a major impact on the quality of life of patients with hATTR. Improvement of qualify of life in patients with hATTR implies periodic symptomatic screening and early management, taking into consideration comorbidities and medication side effects. The specific effect of the disease-modifying treatment on this aspect remains to be unraveled.

Conclusions: Management of autonomic dysfunction in patients with hAATR is feasible and can result in improved qualify of life. Novel disease-modifying treatments for hAATR may contribute to improve autonomic dysfunction, although specific studies are required.
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http://dx.doi.org/10.1007/s10286-019-00624-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763624PMC
September 2019

Renal Infarction and Its Consequences for Renal Function in Patients With Cardiac Amyloidosis.

Mayo Clin Proc 2019 06 15;94(6):961-975. Epub 2019 May 15.

Assistance Publique des Hôpitaux de ParisService de Néphrologie et Transplantation, Créteil, 94000, France; Centre de Référence Maladie Rare Syndrome Néphrotique Idiopathique de l'Enfant et de l'Adulte, Créteil, 94000, France; Réseau Amylose Mondor, Groupe de Recherche Clinique sur les Amyloses Amyloid Research Institute, Centre de référence des amyloses cardiaques, Université Paris Est Créteil, France; Groupe Hospitalier Henri-Mondor/Albert Chenevier, Université Paris Est Créteil, France; and Equipe 21, Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris Est Créteil, France. Electronic address:

Objective: To describe the prevalence of and risk factors for renal infarction (RI) in patients with cardiac amyloidosis.

Patients And Methods: We evaluated 87 patients with cardiac amyloidosis who underwent renal technetium-99m-labeled dimercaptosuccinic acid scintigraphy in the Amyloidosis Referral Center of Henri-Mondor Hospital from October 1, 2015, through February 28, 2018.

Results: Three groups of patients were identified according to the underlying amyloidosis disorder: AL amyloidosis in 24 patients, mutated-transthyretin amyloidosis in 24 patients, and wild-type transthyretin amyloidosis in 39 patients. Patients with wild-type transthyretin amyloidosis were older (P<.001), more likely to be men (P=.02), to have arrhythmic heart diseases (P<.001), and to be receiving anticoagulation treatment (P<.001). Patients with AL amyloidosis had significantly higher N-terminal pro-B-type natriuretic peptide levels (P=.02) and were more likely to have nephrotic syndrome (P<.001). Renal infarction was detected in 18 patients (20.7%), at similar frequencies in the various groups. Baseline urinary protein to creatinine ratio was the only parameter for which a significant difference (P=.03) was found between patients with and without RI diagnoses. The likelihood of RI diagnosis was 47.1% (8 of 17) in the presence of AKI and 14.5% (10 of 69) in its absence (P=.003). Overall, heart transplant-censored patient survival did not differ significantly between patients with and without RI (P=.64), but death- and heart transplant-censored renal survival was significantly lower in patients with RI (P<.001).

Conclusion: Our study suggests that prevalence of RI in patients with cardiac amyloidosis is higher than previously thought, regardless of the underlying amyloidosis disorder. Acute kidney injury in a patient with cardiac amyloidosis should alert clinicians to the possibility of RI.
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http://dx.doi.org/10.1016/j.mayocp.2019.02.012DOI Listing
June 2019

Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS).

Eur Heart J 2019 Apr 1. Epub 2019 Apr 1.

Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.

Aims: Transthyretin amyloidosis (ATTR amyloidosis) is a heterogeneous disorder with cardiac, neurologic, and mixed phenotypes. We describe the phenotypic and genotypic profiles of this disease in continental Western Europe as it appears from the Transthyretin Amyloidosis Survey (THAOS).

Methods And Results: THAOS is an ongoing, worldwide, longitudinal, observational survey established to study differences in presentation, diagnosis, and natural history in ATTR amyloidosis subjects. At data cut-off, 1411 symptomatic subjects from nine continental Western European countries were enrolled in THAOS [1286 hereditary (ATTRm) amyloidosis; 125 wild-type ATTR (ATTRwt) amyloidosis]. Genotypes and phenotypes varied notably by country. Four mutations (Val122Ile, Leu111Met, Thr60Ala, and Ile68Leu), and ATTRwt, were associated with a mainly cardiac phenotype showing symmetric left ventricular (LV) hypertrophy, normal diastolic LV dimensions and volume, and mildly depressed LV ejection fraction (LVEF). Morphologic and functional abnormalities on echocardiogram were significantly more severe in subjects with cardiac (n = 210), compared with a mixed (n = 298), phenotype: higher median (Q1-Q3) interventricular septal thickness [18 (16-21) vs. 16 (13-20) mm; P = 0.0006]; and more frequent incidence of LVEF <50% (38.1 vs. 17.5%; P = 0.0008). Subjects with cardiac mutations or ATTRwt (or cardiac or mixed phenotype) had a lower survival rate than subjects in other genotype (or the neurologic phenotype) categories (P < 0.0001, for both).

Conclusion: ATTR amyloidosis genotypes and phenotypes are highly heterogeneous in continental Western Europe. A geographic map of the different disease profiles and awareness that a subset of subjects have a dominant cardiac phenotype, mimicking hypertrophic cardiomyopathy, at presentation can facilitate the clinical recognition of this underdiagnosed disease.

Trial Registration: ClinicalTrials.gov: NCT00628745.
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http://dx.doi.org/10.1093/eurheartj/ehz173DOI Listing
April 2019

Transthyretin deposition in the eye in the era of effective therapy for hereditary ATTRV30M amyloidosis.

Amyloid 2019 Mar 24;26(1):10-14. Epub 2019 Jan 24.

o Department of Neurology & Neurobiology of Aging , Kanazawa University Graduate School of Medical Science , Kanazawa , Japan.

Background: Ocular abnormalities have been known to occur in hereditary amyloidotic polyneuropathy since the 1950s. While vitreous opacities and scalloped pupils were described early it has become evident that every component of the eye from the conjunctiva to the retinal vasculature can be involved. Reports from the major centres in Japan, Portugal and Sweden, which primarily treat patients with ATTRV30M, have indicated that with the increased longevity seen in patients treated with liver transplantation the frequency of the more severe eye findings, notably vitreous opacities and subsequent glaucoma, are being detected more frequently.

Methods: In an attempt to confirm that the experience was similar in a broader range of locales we performed a survey of ten treatment centres in eight countries to determine the frequency of severe ocular abnormalities (vitreous opacities and glaucoma) in 804 patients with V30M disease and whether there was any relationship to treatment with liver transplantation or the transthyretin stabilizer tafamidis.

Results: The data indicate that the frequency of these abnormalities increases with increasing duration of disease. In patients broadly matched for duration of disease the frequency was higher in subjects who had undergone liver transplantation than in those who were untreated.

Conclusions: Retrospective surveys are subject to a number of potential biases. In this case, the major potential confounders were defining the time of disease onset and physician bias in choice of therapy, particularly regarding the choice of patients and the time in their course when they should undergo liver transplantation, and when and whether they should receive tafamidis. Nonetheless it appears that the incidence of severe ocular abnormalities in V30M subjects from centres around the world is similar to those found in centres in the areas endemic for this variant protein. The incidence increased with duration of disease regardless of therapy with the highest frequencies seen in patients more than ten years after diagnosis who had undergone liver transplantation.
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http://dx.doi.org/10.1080/13506129.2018.1554563DOI Listing
March 2019

An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Expert Opin Pharmacother 2019 Mar 12;20(4):473-481. Epub 2018 Dec 12.

e Department of Neurology , Johns Hopkins University , Baltimore , MD , USA.

Background: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.

Research Design And Methods: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.

Results: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (-5.49) and QoL-DN (-13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.

Conclusions: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.
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http://dx.doi.org/10.1080/14656566.2018.1554648DOI Listing
March 2019

Non-parametric estimation of survival in age-dependent genetic disease and application to the transthyretin-related hereditary amyloidosis.

PLoS One 2018 25;13(9):e0203860. Epub 2018 Sep 25.

Institute of Mathematics (INSMI), National Center for French Research (CNRS), Paris, France.

In genetic diseases with variable age of onset, survival function estimation for the mutation carriers as well as estimation of the modifying factors effects are essential to provide individual risk assessment, both for mutation carriers management and prevention strategies. In practice, this survival function is classically estimated from pedigrees data where most genotypes are unobserved. In this article, we present a unifying Expectation-Maximization (EM) framework combining probabilistic computations in Bayesian networks with standard statistical survival procedures in order to provide mutation carrier survival estimates. The proposed approach allows to obtain previously published parametric estimates (e.g. Weibull survival) as particular cases as well as more general Kaplan-Meier non-parametric estimates, which is the main contribution. Note that covariates can also be taken into account using a proportional hazard model. The whole methodology is both validated on simulated data and applied to family samples with transthyretin-related hereditary amyloidosis (a rare autosomal dominant disease with highly variable age of onset), showing very promising results.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203860PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155453PMC
March 2019

Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis.

N Engl J Med 2018 Jul;379(1):22-31

From the Indiana University School of Medicine, Indianapolis (M.D.B.); Centro de Estudos em Paramiloidose Antônio Rodrigues de Mello, National Amyloidosis Referral Center, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro (M.W.-C.); Amyloidosis Center, Boston University School of Medicine (J.L.B.) and Brigham and Women's Hospital, Harvard Medical School (A.M.S., S.D.S.), Boston; Johns Hopkins University, Baltimore (M.P.); Mayo Clinic, Rochester, MN (P.J.D., W.J.L., M.A.G.); University of California, Irvine, Irvine (A.K.W.); Amyloid Network-Hospital Henri Mondor-Assistance Publique-Hôpitaux de Paris (AP-HP)-Université Paris Est, Créteil, France (V.P.-B.); Institute for Neurologic Research Raúl Carrea, FLENI, Buenos Aires (F.A.B.); Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia (G.M., L.O.), and Unit of Neurology, University Hospital, Messina (G.V.) - both in Italy; Hospital AACD (Associação de Assistência à Criança Deficiente), São Paulo (M.S.); Columbia University Medical Center (T.H.B.) and Mount Sinai Medical Center (P.D.G.), New York; University College London-National Amyloidosis Centre, London (C.W.); Penn Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia (B.M.D.); Centre Hospitaliere Universitaire Bicêtre, AP-HP, Unité 1195, INSERM, Université Paris-Sud, Paris (D.A.); Oregon Health and Science University, Portland (S.B.H.); Centro Hospitalar Lisboa Norte-Hospital de Santa Maria, Lisbon (I.C.), and Centro Hospitalar do Porto, Porto (T.C.) - both in Portugal; Universitätsklinikum Münster, Münster, Germany (H.H.S.); Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (J.M.C.), and Hospital Universitari Vall d'Hebron (J.G.), Barcelona; Auckland City Hospital, Auckland, New Zealand (E.G.); and Ionis Pharmaceuticals, Carlsbad, CA (B.P.M., S.G.H., T.J.K., B.W.M., S.W.J., B.F.B., E.J.A.).

Background: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin.

Methods: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement.

Results: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring.

Conclusions: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .).
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http://dx.doi.org/10.1056/NEJMoa1716793DOI Listing
July 2018

Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.

N Engl J Med 2018 07;379(1):11-21

From Assistance Publique-Hôpitaux de Paris (APHP), National Reference Center for Familial Amyloidotic Polyneuropathy, Centre Hospitalier Universitaire (CHU) Bicêtre, INSERM Unité 1195, Université Paris-Sud, Le Kremlin-Bicêtre (D.A.), the Department of Neuromuscular Disorders and ALS, Hôpital de la Timone, Marseille (S.A.), and the Department of Neurology, Amyloid Network, CHU Henri Mondor-APHP, Créteil (V.P.-B.) - all in France; the National Institute of Medical Sciences and Nutrition-Salvador Zubiran, Mexico City (A.G.-D.); the Department of Clinical Research, eStudySite, San Diego, CA (W.D.O.); the Department of Neurology, National Taiwan University Hospital (C.-C.Y.), and the Department of Neurology, Taipei Veterans General Hospital (K.-P.L.), Taipei, Taiwan; Kumamoto University Hospital, Kumamoto (M.U.), and the Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto (Y.S.) - both in Japan; the Department of Cardiology, University of Heidelberg, Heidelberg (A.V.K.), and Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster (H.H.S.) - both in Germany; University Multiprofile Hospital for Active Treatment, Sofia, Bulgaria (I.T.); Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal (T.C.); the Amyloidosis Center, Department of Medicine, Boston Medical Center (J.L.B.), and Harvard Medical School (S.D.S.), Boston; the Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy (G.V.); the Departments of Neurology and Medicine, Vancouver General Hospital, Vancouver, BC, Canada (M.M.M.); the Department of Nephrology, Hospital Clinic, Barcelona (J.M.C.), and the Balearic Islands Health Research Institute and Hospital Son Llatzer, Palma de Mallorca (J.B.) - all in Spain; the Department of Neurology, Columbia University, College of Physicians and Surgeons, New York (T.H.B.); Samsung Medical Center, Sungkyunkwan University School of Medicine (B.J.K.), and the the Department of Neurology, Konkuk University Medical Center (J.O.), Seoul, South Korea; the Department of Neurology, Istanbul University, Istanbul, Turkey (Y.P.); the Division of Medicine, University College London, London (P.N.H.); Johns Hopkins Bayview Medical Center, Baltimore (M.P.); the Department of Neurology, Mayo Clinic, Rochester, MN (P.J.D.); Alnylam Pharmaceuticals, Cambridge, MA (P.J.G., S.G., J.C., A.L.S., S.V.N., M.T.S., P.P.G., A.K.V., J.A.G.); and the Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden (O.B.S.).

Background: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.

Methods: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status).

Results: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups.

Conclusions: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).
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http://dx.doi.org/10.1056/NEJMoa1716153DOI Listing
July 2018

The value of electrochemical skin conductance measurement using Sudoscan® in the assessment of patients with familial amyloid polyneuropathy.

Clin Neurophysiol 2018 08 29;129(8):1565-1569. Epub 2018 May 29.

Réseau Amylose Henri-Mondor, Hôpital Henri Mondor, Créteil, France; Université Paris Est Créteil, Faculté de Médecine, GRC Institut de Recherche sur l'Amylose, Créteil, France; Assistance Publique - Hôpitaux de Paris, Hôpital Henri Mondor, Service de Neurologie, Créteil, France.

Objective: To reappraise the value of electrochemical skin conductance (ESC) measurement by Sudoscan® to assess the distal involvement of small autonomic fibers in familial amyloid polyneuropathy (FAP) due to various transthyretin (TTR) mutations.

Methods: ESC was measured at both hands and feet in 126 patients with either Val30Met (n = 65) or non-Val30Met (n = 61) TTR mutation. This series included clinically asymptomatic (n = 21) and paucisymptomatic (n = 30) patients, as well as patients with moderate (n = 37) or advanced (n = 38) TTR-FAP.

Results: ESC measures did not differ between patients according to the type of TTR variant and were reduced in 24% of clinically asymptomatic patients, 40% of paucisymptomatic patients, 65% of patients with moderate TTR-FAP, and 92% of patients with advanced TTR-FAP. ESC measures were found to correlate with patients' clinical status, especially assessed by the Neuropathy Impairment Score and Karnofsky Performance Status.

Conclusion: ESC measures well correlate with the severity of TTR-FAP and could provide early marker of the disease.

Significance: ESC measures appear to be relevant to evaluate distal autonomic involvement in the context of amyloidosis.
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http://dx.doi.org/10.1016/j.clinph.2018.05.005DOI Listing
August 2018

Transthyretin familial amyloid polyneuropathy: an update.

J Neurol 2018 Apr 16;265(4):976-983. Epub 2017 Dec 16.

Department of Neurology and Amyloid Network, University Hospital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a progressive, fatal, inherited disorder first identified in Portugal and now recognized in all continents. Over the past decade, thanks to the availability of the genetic test, our knowledge on the range of clinical expressions of this disorder has expanded, including different patterns and progression rates of the neuropathy, as well as aspects of the cardiomyopathy, which can be prominent. In the mean time, new tools are being developed to detect earlier TTR amyloid deposition such as cardiac scintigraphy with technetium-labelled pyrophosphate tracers or small nerve fiber alterations from skin biopsies, or using neurophysiological approaches as well as magnetic resonance neurography (MRN). Such refinements, along with an increased awareness of the disease, should reduce the diagnostic delay and facilitate early treatment. In this regard, thanks to a better understanding of the TTR amyloid formation, major advances have been made, allowing for therapeutic developments which are less invasive than liver transplantation (LT). TTR stabilizer drugs are safe and seem to delay the disease progression in some groups of patients. Indeed, positive results have just been released from 2 phase III trials on TTR gene modifiers, namely silencing RNA and antisense oligonucleotide therapies. These recent advances open a new area in the field with the hope that we can safely bring about long-term stabilization of the disease. Furthermore, immunotherapies targeting the amyloid deposits are being explored.
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http://dx.doi.org/10.1007/s00415-017-8708-4DOI Listing
April 2018

Apical sparing pattern of left ventricular myocardial Tc-HMDP uptake in patients with transthyretin cardiac amyloidosis.

J Nucl Cardiol 2018 12 26;25(6):2072-2079. Epub 2017 Apr 26.

Mondor Amyloidosis Network, Créteil, France.

Background: A decreased longitudinal strain in basal segments with a base-to-apex gradient has been described in patients with cardiac amyloidosis (CA).

Objectives: Aim was to investigate the left ventricular (LV) regional distribution of early-phase Tc-Hydroxymethylene diphosphonate (Tc-HMDP) uptake in patients with transthyretin-related cardiac amyloidosis (TTR-CA).

Methods: All patients underwent a whole-body planar Tc-HMDP scintigraphy acquired at 10-min post-injection (early-phase) followed by a thorax SPECT/CT. The segmental uptake (expressed as % of maximal myocardial HMDP uptake) was investigated on the AHA 17-segment model and 3-segment model (basal, mid-cavity, apical).

Results: Sixty-one TTR-CA patients were included of whom 29 were wild-type (wt-TTR-CA) and 32 had hereditary TTR-CA (m-TTR-CA). Early myocardial Tc-HMDP uptake occurred in all TTR-CA. In all patients, segmental analysis of the LV myocardial distribution of Tc-HMDP uptake showed an increased median uptake (interquartile range) in basal/mid-cavity segments compared to the lowest median uptake of apical segments (respectively, 79% [72%-86%] vs. 72% [64%-81%]; P < 10). This pattern was similar in wt-TTR-CA group (78% [70%-84%] vs. 70% [61%-81%]; P < 10), in m-TTR-CA group (80% [74%-86%] vs. 73 [66%-82%]; P < 10) and remained constant independently of the TTR mutation subtype with P ranging 10 to 0.03.

Conclusions: Early-phase myocardial scintigraphy identified regional distribution of Tc-HMDP uptake characterized by a base-to-apex gradient, corroborating echocardiographic, and cardiac magnetic resonance findings. This apical sparing pattern was similar across TTR-CA and TTR mutation subtypes.
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http://dx.doi.org/10.1007/s12350-017-0894-zDOI Listing
December 2018

Assessing mNIS+7 and international neurologists' proficiency in a familial amyloidotic polyneuropathy trial.

Muscle Nerve 2017 Nov 7;56(5):901-911. Epub 2017 Apr 7.

Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905, USA.

Introduction: Polyneuropathy signs (Neuropathy Impairment Score, NIS), neurophysiologic tests (m+7 ), disability, and health scores were assessed in baseline evaluations of 100 patients entered into an oligonucleotide familial amyloidotic polyneuropathy (FAP) trial.

Methods: We assessed: (1) Proficiency of grading neurologic signs and correlation with neurophysiologic tests, and (2) clinometric performance of modified NIS+7 neurophysiologic tests (mNIS+7 ) and its subscores and correlation with disability and health scores.

Results: The mNIS+7 sensitively detected, characterized, and broadly scaled diverse polyneuropathy impairments. Polyneuropathy signs (NIS and subscores) correlated with neurophysiology tests, disability, and health scores. Smart Somatotopic Quantitative Sensation Testing of heat as pain 5 provided a needed measure of small fiber involvement not adequately assessed by other tests.

Conclusions: Specially trained neurologists accurately assessed neuropathy signs as compared to referenced neurophysiologic tests. The score, mNIS+7 , broadly detected, characterized, and scaled polyneuropathy abnormality in FAP, which correlated with disability and health scores. Muscle Nerve 56: 901-911, 2017.
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http://dx.doi.org/10.1002/mus.25563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500439PMC
November 2017

Long-term treatment of transthyretin familial amyloid polyneuropathy with tafamidis: a clinical and neurophysiological study.

J Neurol 2017 Feb 22;264(2):268-276. Epub 2016 Nov 22.

Amyloid Network, Henri Mondor University Hospital, AP-HP, Créteil, France.

Tafamidis is a transthyretin (TTR) stabilizer recently approved to slow the neurologic impairment in TTR familial amyloid polyneuropathy (TTR-FAP). The pivotal studies on Tafamidis reported encouraging results on the short term, in the early onset Val30Met-TTR-FAP patients at an early stage of the neuropathy. However, the effect of the drug in the non-Val30Met patients, at a more advanced stage of the disease and on the long term, is less known. In this study, we report the effect of Tafamidis in 43 TTR-FAP patients with a variety of pathogenic mutations, including 53% of non-Val30Met variants, at different stages of neuropathy followed on the long term. General and neurological assessment was performed in a standardized protocol every 6-12 months along with neurophysiological variables, including testing of small nerve fibres. The mean follow-up under treatment was 2 years with a subset of 26 patients treated for 3 years. Overall, Tafamidis was well tolerated. A significant clinical deterioration of the neuropathy and the patient's general condition was observed across the 3 years follow-up, although neurophysiological parameters remained stable for the first 2 years. In contrast, patients had a significant increase of BMI under treatment. Deterioration of the neuropathy correlated to an older age at disease onset or treatment initiation and to poor clinical status at baseline. A higher BMI at baseline was associated with a lower progression of the neuropathy. About one-third of the patients who received 3 years of tafamidis had still preserved walking capacity or good clinical condition, suggesting that tafamidis slowed the disease progression in some patients. Overall, our work shows that tafamidis is well tolerated in TTR-FAP but does not prevent the steady progression of the neuropathy on the long term. Age, neurologic status, and general condition at baseline appear to be best predictors of tafamidis efficacy on the neurological function.
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http://dx.doi.org/10.1007/s00415-016-8337-3DOI Listing
February 2017

Current and Future Treatment Approaches in Transthyretin Familial Amyloid Polyneuropathy.

Curr Treat Options Neurol 2016 Dec;18(12):53

Service de Neurologie, CHU Henri Mondor, 51 avenue de Lattre de Tassigny, 94000, Créteil, France.

Opinion Statement: Treatment of transthyretin familial amyloid polyneuropathy (TTR FAP) must be tailored to disease stage. Patients with early stage disease (i.e., without major impairment in walking ability), especially younger patients, should be referred as soon as possible for liver transplantation (LT) in the absence of major comorbid conditions. LT remains the most effective treatment option to date and should be offered to these patients as early as possible. Bridging therapy with an oral TTR stabilizer (tafamidis or diflunisal, according to local access to these treatments) should be started as soon as the diagnosis of TTR FAP is established. Early stage patients who do not wish to or have contraindications to LT should be treated with an oral TTR stabilizer or get access to the newly developed therapeutic options (IONIS TTR-Rx, patisiran, doxycycline/TUDCA). Late stage patients (presenting with significant walking impairment) are usually older and notoriously difficult to treat. They should be offered an oral TTR stabilizer but are not candidates for LT due to a significant rate of perioperative complications and increased risk of progressive neurological and especially cardiac disease despite LT. Access to the different therapies in development should also be considered depending on respective inclusion and exclusion criteria. The abovementioned treatment options were mostly validated in Val30Met mutation patients, but should also be offered to non-Val30Met patients, although mortality rates after LT are higher in these patients. Treatment decisions should be made on an individual basis. Screening for heart, eye, and renal involvement is mandatory for every patient at disease diagnosis and regularly thereafter, even in transplanted patients. Symptomatic treatment should be offered as needed, as well as genetic counseling to at-risk family members. Asymptomatic mutation carriers should benefit from regular screening for early symptoms of disease. Current therapeutic management of TTR FAP will hopefully be changed in the near future with data from the ongoing phase 2/3 studies testing the TTR gene silencing agents. In the longer term, it is likely that combined therapeutic approaches will be necessary to reverse the disease process.
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http://dx.doi.org/10.1007/s11940-016-0436-zDOI Listing
December 2016

Early-phase myocardial uptake intensity of Tc-HMDP vs Tc-DPD in patients with hereditary transthyretin-related cardiac amyloidosis.

J Nucl Cardiol 2018 02 1;25(1):217-222. Epub 2016 Nov 1.

Mondor Amyloidosis Network, 94000, Créteil, France.

Background: This study sought to compare the intensity of early-phase myocardial uptake of two phosphonate-based radiotracers, Tc-hydroxymethylene diphosphonate (HMDP) and Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), in patients with hereditary transthyretin-related cardiac amyloidosis (TTR-CA).

Methods: Six patients with biopsy-proven diagnosis of TTR-CA and characteristic amyloid fibril composition underwent early-phase Tc-HMDP myocardial scintigraphy as part of their routine workup; they were later assessed by Tc-DPD scintigraphy after having signed informed written consent. Heart-to-mediastinum-ratio was measured at both time points as well as regional distribution on 17-segment analysis.

Results: All patients had an H/M ratio >1.28 on both imaging. Tc-DPD uptake was slightly higher than Tc-HMDP uptake in 3 patients, but no statistical difference was found (P = 0.13). Regional distribution of the two radiotracers was well correlated on bull's eyes analysis, with only slight underestimation of Tc-DPD uptake in the anterior/apical segments, compared with Tc-HMDP.

Conclusion: Tc-HMDP and Tc-DPD show comparable myocardial uptake intensity on early-phase scintigraphy and can be used alternatively for the diagnosis of TTR-CA.
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http://dx.doi.org/10.1007/s12350-016-0707-9DOI Listing
February 2018

[Cardiac amyloidosis: How to recognize them and manage them?]

Presse Med 2016 Oct 1;45(10):845-855. Epub 2016 Aug 1.

CHU Henri-Mondor, service de cardiologie, 94010 Créteil cedex, France; CHU Henri-Mondor, réseau Amylose Mondor, 94010 Créteil cedex, France; Université Paris-Est-Créteil, faculté de médecine, 94010 Créteil cedex, France; CHU Henri-Mondor, GRC-ARI, DHU-ATVB, Inserm U955, IMRB, 94010 Créteil cedex, France.

Cardiac amyloidosis must be suspected in all cases of hypertrophic cardiomyopathy with preserved left ventricular ejection fraction to allow specific management. Final diagnosis needs pathological evidence, but bone scintigraphy may be an alternative for TTR amyloidosis. Invasive samplings are limited by new tools. Amyloidosis typing is required to start specific therapies if possible. Main specific treatments that are available are chemotherapy for AL; transthyretin stabilizer or gene therapy, studied for TTR-related cardiac amyloidosis.
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http://dx.doi.org/10.1016/j.lpm.2016.07.001DOI Listing
October 2016

Identification of prognostic markers in transthyretin and AL cardiac amyloidosis.

Amyloid 2016 Sep 20;23(3):194-202. Epub 2016 Sep 20.

g Department of Cardiology , Dupuytren Teaching Hospital , Limoges , France.

Background: The prognosis of amyloidosis is known to depend heavily on cardiac function and may be improved by identifying patients at highest risk for adverse cardiac events.

Aims: Identify predictors of mortality in patients with cardiac light-chain amyloidosis (AL), hereditary transthyretin amyloidosis (m-TTR), or wild-type transthyretin amyloidosis (WT-TTR) to prompt physician to refer these patients to dedicated centers.

Methods And Results: Observational study. About 266 patients referred for suspected cardiac amyloidosis (CA) in two French university centers were included. About 198 patients had CA (AL = 118, m-TTR = 57, and WT-TTR = 23). Their median (25th-75th percentile) age, NT-proBNP left ventricular ejection fraction were, respectively, 68 years (59-76), 2339 pg mL (424-5974), and 60% (48-66). About 31% were in NYHA class III-IV. Interventricular septal thickness was greater in the m-TTR and WT-TTR groups than in the AL group (p < 0.0001). Median follow-up in survivor was 26 months (15-44) and 87 (44%) patients died. By multivariate analysis, independent predictors of mortality for AL amyloidosis were the following: age, cardiac output and NT-proBNP; for TTR amyloidosis was: NT-proBNP. When all amyloidosis were combined NT-proBNP, low cardiac output and pericardial effusion were independently associated with mortality.

Conclusion: NT-proBNP is a strong prognosticator in the three types of cardiac amyloidosis. High NT-proBNP, low cardiac output, and pericardial effusion at the time of screening should prompt physician to refer the patients to amyloidosis referral center.
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http://dx.doi.org/10.1080/13506129.2016.1221815DOI Listing
September 2016

Prognostic value of right ventricular systolic function in cardiac amyloidosis.

Amyloid 2016 Sep 27;23(3):158-167. Epub 2016 Jun 27.

a Department of Cardiology.

Background: Right ventricular (RV) dysfunction is a strong predictor of poor outcomes in heart failure. Its prognostic meaning in cardiac amyloidosis (CA) is under-investigated.

Methods: Hundred and twenty nine patients with suspected CA and an interventricular septum thickness (IVST) ≥ 12 mm underwent echocardiography with measurement of left ventricular (LV) and RV longitudinal strain (LS), late gadolinium-enhancement (LGE) cardiac MRI, and standard evaluation.

Results: Among 82 confirmed CA, types were immunoglobulin light chain (AL, n = 26), hereditary transthyretin (m-TTR, n = 37) and senile (WT-TTR, n = 19). Compared to those without, CA patients had significantly lower RV fractional shortening (RV-FS), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler systolic velocity, and global RV-LS, without any difference among the CA types. RV-LGE, observed in 62% of CA patients, was associated with lower global and basal RV-FS. Median follow-up was 8(2; 16) months. Using multivariate analysis, NYHA-class and low TAPSE independently predicted major adverse cardiac event (MACE) defined as death, heart transplantation and acute heart failure. Independent determinants of TAPSE < 14 mm, the best cut-off value, were LV ejection fraction (LVEF), estimated filling pressure (E/E'), NT-proBNP and pulmonary artery pressure, but not RV-LGE.

Conclusions: RV dysfunction is common in CA. Its routine evaluation by a simple TAPSE may be an aid in assessing the prognosis of CA patients.
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http://dx.doi.org/10.1080/13506129.2016.1194264DOI Listing
September 2016

Outcome and incidence of appropriate implantable cardioverter-defibrillator therapy in patients with cardiac amyloidosis.

Int J Cardiol 2016 Nov 1;222:562-568. Epub 2016 Aug 1.

AP-HP, University Hospital Henri Mondor, Department of Cardiology, Creteil, France; UPEC, AP-HP Henri-Mondor Teaching Hospital, Inserm U955, IMRB GRC Mondor Amyloidosis Network, Inserm Clinical Investigation Center 1430, Créteil F-94000, France.

Background: Cardiac amyloidosis (CA) is associated with a poor prognosis with the proposed mechanism of sudden cardiac death in the majority of patients being pulseless electrical activity. However, the incidence of ventricular arrhythmias (VA) and implantable cardioverter-defibrillator (ICD) indications in CA patients are unclear. We performed a detailed evaluation of our CA population undergoing ICD implantation and assessed appropriate ICD therapy and survival predictors.

Methods: We included consecutive patients from June 2008 to November 2014 in five centers. ICDs were systematically interrogated and clinical data recorded during follow-up.

Results: Forty-five patients (35 males, mean age 66±12years) with CA who underwent ICD implantation (84.4% primary prevention) were included. CA types were hereditary transthyretin in 27 patients (60%), light chain (AL) in 12 (27%) and senile in 6 (13%). After a mean follow-up of 17±14months, 12 patients (27%) had at least 1 appropriate ICD therapy occurring after 4.7±6.6months. Patients with or without ICD therapy had no significant differences in baseline characteristics, amyloidosis type, LVEF, and type of prevention although there was a trend towards a better 2D global longitudinal strain in patients with ICD therapy (P=0.08). Over the follow-up, 12 patients died (27%) and 6 underwent cardiac transplantation (13%). From multivariate analysis a worse prognosis was associated with higher NT-proBNP level (>6800pg/mL, HR=5.5[1.7-17.8]) and AL type (HR=4.9[1.5-16.3]).

Conclusions: Appropriate ICD therapies are common (27%) in CA patients. No specific strong VA predictor could be identified. However, patients with advanced heart disease, especially with AL-CA, display a poorer outcome.
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http://dx.doi.org/10.1016/j.ijcard.2016.07.254DOI Listing
November 2016

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey).

J Am Coll Cardiol 2016 07;68(2):161-72

University of Bologna, Bologna, Italy.

Background: Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.

Objectives: The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.

Methods: Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).

Results: U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.

Conclusions: In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).
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http://dx.doi.org/10.1016/j.jacc.2016.03.596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940135PMC
July 2016

Prevalence, Severity, and Prognostic Value of Sleep Apnea Syndromes in Cardiac Amyloidosis.

Sleep 2016 Jul 1;39(7):1333-41. Epub 2016 Jul 1.

Cardiology Department, AP-HP Henri Mondor Teaching Hospital, Créteil, France.

Study Objectives: To assess prevalence, severity, and prognostic value of sleep-disordered breathing (SDB), in the three main cardiac amyloidosis (CA) types, i.e., light-chain (AL), transthyretin-related familial (m-TTR), or senile (WT-TTR).

Methods: Patients consecutively referred for CA diagnosis work-up underwent cardiac assessment and nocturnal polygraphy. SDB was defined as apnea-hypopnea index (AHI) ≥ 5/h. Multivariate analysis was used to identify predictors of a major adverse cardiac event (MACE) defined as death, heart transplantation and acute heart failure.

Results: Seventy CA patients were included (31 AL, 22 m-TTR, 17 WT-TTR). The mean ± standard deviation age and left ventricular ejection fraction were 71 ± 12 years and 49% ± 13% and median (interquartile range) N terminal pro brain natriuretic peptide (NT-proBNP) was 3,932 (1,607; 7,028) pg/mL. The prevalence of SDB was 90% without difference between amyloidosis types. SDB was central in 27% and obstructive in 73%. AL had less frequent severe SDB compared to m-TTR and WT-TTR (P = 0.015) but longer time with peripheral capillary oxygen saturation (SpO2) < 90% (P = 0.037). After a median follow-up of 7.5 (2.8; 14.9) months, 49% patients experienced MACE. Time with nocturnal SpO2 < 90% was the only independent predictor of MACE. The best-identified threshold was 30 min. Values > 30 min were associated with bad prognosis (Log-rank χ(2): 8.01, P value = 0.005). Using binomial logistic regression, determinants of time with nocturnal SpO2 < 90% were New York Heart Association class (P = 0.011), and log-NT-proBNP (P = 0.04) but not AHI.

Conclusions: In CA population, prevalence of SDB is high (90%) and dominated by the obstructive pattern. Bad prognosis in this population was driven by nocturnal desaturation, reflecting heart failure severity and respiratory involvement.
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http://dx.doi.org/10.5665/sleep.5958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909615PMC
July 2016

Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.

Neurol Ther 2016 Jun 19;5(1):1-25. Epub 2016 Feb 19.

Massachusetts General and McLean Hospitals, Harvard Medical School, Boston, MA, USA.

Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis.
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http://dx.doi.org/10.1007/s40120-016-0040-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919130PMC
June 2016

Clinical, ECG and echocardiographic clues to the diagnosis of TTR-related cardiomyopathy.

Open Heart 2016;3(1):e000289. Epub 2016 Feb 8.

Amyloidosis Center, Department of Cardiology , Heidelberg University , Heidelberg , Germany.

Background: Signs of cardiac transthyretin (TTR) amyloidosis (ATTR) in patients with echocardiographic increase in interventricular septal thickness (IVST) are lacking.

Objectives: To identify clinical and ECG/echocardiographic signs associated with increased IVST in ATTR.

Methods: Analysis of patients with baseline echocardiography in the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry (N=1682). Patients were categorised into IVST classes according to the American Society of Echocardiography classification adapted to gender (ie, normal, mild, moderate, severe); then into two combined IVST classes (normal-mild and moderate-severe).

Results: 425 patients were included: 336 with a TTR mutation (m-TTR) and 89 with wild-type TTR (WT-TTR). 72% were men. Median (25th, 75th centile) age was 62 (45, 72) years. Non-Val30Met and WT-TTR were frequent in moderate (41% and 35%) and severe (50% and 33%) IVST classes. Median IVST was 15 mm (14, 16) (moderate) and 20 mm (18, 22) (severe). In the combined moderate-severe class, 85% of patients were ≥55 years of age; 81% were men; 86% had blood pressure <140 mm Hg; and 77% had increased right ventricle thickness (≥7 mm). Up to 66% of patients had cardiac sparkling. Systolic dysfunction (left ventricular ejection fraction <50%), restrictive pattern and low voltage were less frequent, and observed in 49%, 18% and 33% of patients, respectively.

Conclusions: Increased IVST, especially in men ≥55 years with normal systolic blood pressure, increase in right ventricle free wall and valve thicknesses, and sparkling, should alert practitioners to the possibility of ATTR. Absence of restrictive pattern and low voltage should not rule out the suspicion.

Trial Registration Number: NCT00628745 (clinicaltrials.gov).
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http://dx.doi.org/10.1136/openhrt-2015-000289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746524PMC
February 2016

Causes and Consequences of Longitudinal LV Dysfunction Assessed by 2D Strain Echocardiography in Cardiac Amyloidosis.

JACC Cardiovasc Imaging 2016 Feb 6;9(2):126-38. Epub 2016 Jan 6.

UPEC, Créteil, France; Mondor Amyloidosis Network, Créteil, France; Department of Cardiology, AP-HP, Henri-Mondor Teaching Hospital, Créteil, France; INSERM U955, GRC Amyloid Research Institute, Créteil, France; DHU ATVB, Créteil, France; INSERM Clinical Investigation Center 006, Créteil, France. Electronic address:

Objectives: The aim of this study was to compare left ventricular longitudinal strain (LS) evaluated by 2-dimensional echocardiography with cardiac magnetic resonance (CMR) in cardiac amyloidosis (CA), establish correlations between histological and imaging findings, and assess the prognostic usefulness of LS measurement and CMR.

Background: CA is a condition with a poor prognosis due chiefly to 3 forms of amyloidosis: light-chain amyloidosis (AL), hereditary transthyretin (M-TTR), and wild-type transthyretin (WT-TTR). Two-dimensional echocardiography measurement of LS has been reported to detect early left ventricular systolic dysfunction. The pathophysiological underpinnings, regional distribution, and prognostic significance of LS in CA are unclear.

Methods: All patients underwent echocardiography, and 53 underwent CMR. The native hearts of the 3 patients who received heart transplants were subjected to histological examination. For each of the 17 left ventricular segments in the American Heart Association model, we evaluated LS, late gadolinium enhancement (LGE) by CMR, and cardiac amyloid deposition. Univariate and multivariate analyses were performed at 6 months to identify variables associated with major adverse cardiac events (MACE).

Results: We studied 79 patients with CA; 26 had AL, 36 M-TTR, and 17 WT-TTR. Mean LS was -10 ± 4%. Both LS and amyloid deposits showed a basal-to-apical gradient. The mean LS and number of segments with LGE were similar across the 3 CA types. LS correlated with LGE and amyloid burden (r = 0.72). LGE was seen in the 6 basal segments in all WT-TTR patients. During the median follow-up of 11 months (range 4 to 17 months), 36 (46%) patients experienced MACE. Independent predictors of MACE were apical LS (cutoff, -14.5%), N-terminal pro-B-type natriuretic peptide (cutoff, 4,000 ng/l), and New York Heart Association functional class III to IV heart failure.

Conclusions: Basal-to-apical LS abnormalities are similar across CA types and reflect the amyloid burden. Apical LS independently predicts MACE.
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http://dx.doi.org/10.1016/j.jcmg.2015.05.014DOI Listing
February 2016

Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis.

J Am Coll Cardiol 2015 Dec;66(21):2451-2466

Department of Molecular Medicine, University of Pavia, Pavia, Lombardy, Italy.

Transthyretin amyloidosis is a fatal disorder that is characterized primarily by progressive neuropathy and cardiomyopathy. It occurs in both a mutant form (with autosomal dominant inheritance) and a wild-type form (with predominant cardiac involvement). This article guides clinicians as to when the disease should be suspected, describes the appropriate diagnostic evaluation for those with known or suspected amyloidosis, and reviews the interventions currently available for affected patients.
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http://dx.doi.org/10.1016/j.jacc.2015.09.075DOI Listing
December 2015