{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:44:48Z","timestamp":1790790288025,"version":"4.1.0"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2018,8,2]],"date-time":"2018-08-02T00:00:00Z","timestamp":1533168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"},{"start":{"date-parts":[[2018,8,2]],"date-time":"2018-08-02T00:00:00Z","timestamp":1533168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer Inc.","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["GR-2011-02352282"],"award-info":[{"award-number":["GR-2011-02352282"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministry of Health, Italy","doi-asserted-by":"publisher","award":["GR\u20102011\u201002352282"],"award-info":[{"award-number":["GR\u20102011\u201002352282"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Cardiac amyloidosis remains a great challenge for the cardiologist. One of the three main aetiological forms, transthyretin-related hereditary amyloidosis (ATTRm), can present with several phenotypes, depending mainly on the specific mutation. We aimed to characterize the phenotype of patients with ATTRm due to Ile68Leu mutation, comparing them to patients with wild-type transthyretin amyloidosis (ATTRwt).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Data of 67 Ile68Leu ATTRm patients from two Italian referral centres (Bologna and Florence) were retrospectively analysed and compared to those of 82 ATTRwt patients. Fifty-five unaffected mutation carriers were also analysed. Cumulative disease onset was 50% at age 71. A total of 56\/67 (84%) patients had a predominantly cardiac phenotype at presentation with concentric increase in left ventricular wall thickness [median 17 mm], and normal or near normal left ventricular ejection fraction (79% of patients). Low QRS voltages were present only in 29% of patients but voltage\/mass ratio was low (0.5). Carpal tunnel syndrome was noted in 43%. The overall phenotypic profile was similar to ATTRwt but Ile68Leu ATTRm patients typically presented younger (median 71 vs. 78\u2009years) and were more likely to have (mild) symptomatic neurological involvement (19% vs. 2%). Male prevalence was 44% in unaffected mutation carriers and 78% in affected patients. Age-adjusted survival was comparable between groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Ile68Leu ATTRm is a cause of familial amyloidotic cardiomyopathy endemic in central-northern Italy and presents as hypertrophic\/restrictive cardiomyopathy quite similar to ATTRwt. Male preponderance is present in affected patients but not in unaffected mutation carriers. Age-adjusted survival is similar to ATTRwt.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.1285","type":"journal-article","created":{"date-parts":[[2018,8,6]],"date-time":"2018-08-06T17:55:13Z","timestamp":1533578113000},"page":"1417-1425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Phenotypic Profile of Ile68Leu Transthyretin Amyloidosis: An Underdiagnosed Cause of Heart Failure"],"prefix":"10.1093","volume":"20","author":[{"given":"Christian","family":"Gagliardi","sequence":"first","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Perfetto","sequence":"additional","affiliation":[{"name":"Tuscan Regional Amyloid Center, Careggi University Hospital , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Lorenzini","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]},{"name":"Institute for Cardiovascular Science, University College London, and Barts Heart Centre, St. Bartholomew's Hospital , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Ferlini","sequence":"additional","affiliation":[{"name":"Section of Medical Genetics, Department of Diagnostic and Experimental Medicine, University of Ferrara \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Salvi","sequence":"additional","affiliation":[{"name":"Division of Neurology, IRCCS Institute of Neurological Sciences, Bellaria Hospital , Bologna ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnese","family":"Milandri","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina Candida","family":"Quarta","sequence":"additional","affiliation":[{"name":"National Amyloidosis Centre, University College London (Royal Free Campus) , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Taborchi","sequence":"additional","affiliation":[{"name":"Tuscan Regional Amyloid Center, Careggi University Hospital , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Bartolini","sequence":"additional","affiliation":[{"name":"Tuscan Regional Amyloid Center, Careggi University Hospital , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Frusconi","sequence":"additional","affiliation":[{"name":"Tuscan Regional Amyloid Center, Careggi University Hospital , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Martone","sequence":"additional","affiliation":[{"name":"Tuscan Regional Amyloid Center, Careggi University Hospital , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele Mario","family":"Cinelli","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Foffi","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Letizia Bacchi","family":"Reggiani","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gioele","family":"Fabbri","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Cataldo","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cappelli","sequence":"additional","affiliation":[{"name":"Tuscan Regional Amyloid Center, Careggi University Hospital , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Rapezzi","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna \u00a0","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,8,2]]},"reference":[{"key":"2026011721252573900_ejhf1285-bib-0001","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1136\/heartjnl-2016-309914","article-title":"Amyloid heart disease: genetics translated into disease-modifying therapy","volume":"103","author":"Sperry","year":"2017","journal-title":"Heart"},{"key":"2026011721252573900_ejhf1285-bib-0002","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1056\/NEJMra023144","article-title":"Molecular mechanisms of amyloidosis","volume":"349","author":"Merlini","year":"2003","journal-title":"N Engl J Med"},{"key":"2026011721252573900_ejhf1285-bib-0003","doi-asserted-by":"crossref","first-page":"E2403","DOI":"10.1002\/humu.22619","article-title":"Online registry for mutations in hereditary amyloidosis including nomenclature recommendations","volume":"35","author":"Rowczenio","year":"2014","journal-title":"Hum Mutat"},{"key":"2026011721252573900_ejhf1285-bib-0004","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10741-015-9480-0","article-title":"Cardiac amyloidosis: the great pretender","volume":"20","author":"Rapezzi","year":"2015","journal-title":"Heart Fail Rev"},{"key":"2026011721252573900_ejhf1285-bib-0005","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1056\/NEJM199702133360703","article-title":"Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans","volume":"336","author":"Jacobson","year":"1997","journal-title":"N Engl J Med"},{"key":"2026011721252573900_ejhf1285-bib-0006","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1056\/NEJMoa1404852","article-title":"V122I transthyretin variant in elderly black Americans","volume":"372","author":"Quarta","year":"2015","journal-title":"N Engl J Med"},{"key":"2026011721252573900_ejhf1285-bib-0007","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/gim.2016.200","article-title":"Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans","volume":"19","author":"Buxbaum","year":"2017","journal-title":"Genet Med"},{"key":"2026011721252573900_ejhf1285-bib-0008","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0002-9343(92)90672-X","article-title":"A Danish kindred with familial amyloid cardiomyopathy revisited: identification of a mutanttransthyretin-methionine111 variant in serum from patients and carriers","volume":"93","author":"Ranl\u00f8v","year":"1992","journal-title":"Am J Med"},{"key":"2026011721252573900_ejhf1285-bib-0009","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1093\/eurheartj\/ehr383","article-title":"Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant","volume":"33","author":"Sattianayagam","year":"2012","journal-title":"Eur Heart J"},{"key":"2026011721252573900_ejhf1285-bib-0010","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1093\/eurheartj\/ehx043","article-title":"Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths","volume":"38","author":"Gonz\u00e1lez-L\u00f3pez","year":"2017","journal-title":"Eur Heart J"},{"key":"2026011721252573900_ejhf1285-bib-0011","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1093\/eurheartj\/ehs123","article-title":"Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective","volume":"34","author":"Rapezzi","year":"2013","journal-title":"Eur Heart J"},{"key":"2026011721252573900_ejhf1285-bib-0012","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jacc.2016.03.596","article-title":"Genotype and phenotype of transthyretin cardiac amyloidosis in the United States: the Transthyretin Amyloid Outcome Survey (THAOS)","volume":"68","author":"Maurer","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"2026011721252573900_ejhf1285-bib-0013","first-page":"p88","volume-title":"Amyloid and Amyloidosis","author":"Coutinho","year":"1980"},{"key":"2026011721252573900_ejhf1285-bib-0014","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.amjcard.2004.10.028","article-title":"Electrocardiographic findings in primary systemic amyloidosis and biopsy-proven cardiac involvement","volume":"95","author":"Murtagh","year":"2005","journal-title":"Am J Cardiol"},{"key":"2026011721252573900_ejhf1285-bib-0015","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1016\/j.echo.2005.10.005","article-title":"Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology","volume":"18","author":"Lang","year":"2005","journal-title":"J Am Soc Echocardiogr"},{"key":"2026011721252573900_ejhf1285-bib-0016","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1161\/01.CIR.57.6.1140","article-title":"Echocardiographic diagnosis of left ventricular hypertrophy","volume":"57","author":"McFarland","year":"1978","journal-title":"Circulation"},{"key":"2026011721252573900_ejhf1285-bib-0017","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3109\/13506129.2014.994202","article-title":"The myocardial contraction fraction is superior to ejection fraction in predicting survival in patients with AL cardiac amyloidosis","volume":"22","author":"Tendler","year":"2015","journal-title":"Amyloid"},{"key":"2026011721252573900_ejhf1285-bib-0018","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1096\/fasebj.6.10.1353040","article-title":"Molecular strategies in genetic diagnosis of transthyretin-related hereditary amyloidosis","volume":"6","author":"Ferlini","year":"1992","journal-title":"FASEB J"},{"key":"2026011721252573900_ejhf1285-bib-0019","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1001\/archinte.165.20.2429","article-title":"Female sex as a possible protective factor from myocardial involvement in transthyretin-related amyloidoses","volume":"165","author":"Rapezzi","year":"2005","journal-title":"Arch Intern Med"},{"key":"2026011721252573900_ejhf1285-bib-0020","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3109\/13506129.2010.483114","article-title":"Heart complications in familial transthyretin amyloidosis: impact of age and gender","volume":"17","author":"H\u00f6rnsten","year":"2010","journal-title":"Amyloid"},{"key":"2026011721252573900_ejhf1285-bib-0021","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0143456","article-title":"Amyloid cardiomyopathy in hereditary transthyretin V30M amyloidosis \u2013 impact of sex and amyloid fibril composition","volume":"10","author":"Arvidsson","year":"2015","journal-title":"PLoS One"},{"key":"2026011721252573900_ejhf1285-bib-0022","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.jacc.2016.09.987","article-title":"Val122Ile mt-ATTR has a worse survival than wt-ATTR cardiac amyloidosis","volume":"69","author":"Singh","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"2026011721252573900_ejhf1285-bib-0023","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.jacc.2016.11.047","article-title":"Reply: Val122Ile mt-ATTR has a worse survival than wt-ATTR cardiac amyloidosis","volume":"69","author":"Maurer","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"2026011721252573900_ejhf1285-bib-0024","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.jacc.2016.06.033","article-title":"Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system","volume":"68","author":"Grogan","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"2026011721252573900_ejhf1285-bib-0025","doi-asserted-by":"crossref","DOI":"10.1093\/eurheartj\/ehx589","article-title":"A new staging system for cardiac transthyretin amyloidosis","volume":"39","author":"Gillmore","year":"2018","journal-title":"Eur Heart J"}],"container-title":["European Journal of Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fejhf.1285","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/20\/10\/1417\/66268431\/eurjhf_20_10_1417.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/20\/10\/1417\/66268431\/eurjhf_20_10_1417.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T02:27:42Z","timestamp":1768703262000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjhf\/article\/20\/10\/1417\/8414608"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,2]]},"references-count":25,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,8,2]]},"published-print":{"date-parts":[[2018,10,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ejhf.1285","relation":{},"ISSN":["1388-9842","1879-0844"],"issn-type":[{"value":"1388-9842","type":"print"},{"value":"1879-0844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,10]]},"published":{"date-parts":[[2018,8,2]]},"assertion":[{"value":"2018-05-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-06-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}