Afro-Caribbean Heart Failure in the UK: Aetiology ...



Afro-Caribbean Heart Failure in the UK: Etiology, Outcomes and ATTR V122I Cardiac Amyloidosis Short title: Dungu UK Afro-Caribbean Heart Failure & ATTR V122IAuthors: Jason N Dungu PhD MRCP1,2, Sofia A Papadopoulou MD1, Katharine Wykes MBBS1, Ihtisham Mahmood MBBS1, Joseph Marshall MBBS1, Oswaldo Valencia MSc MD 1, Marianna Fontana MD2, Carol J Whelan MD2, Julian D Gillmore MD PhD FRCP2, Philip N Hawkins PhD FRCP FRCPath FMedSci2, Lisa J Anderson MD FRCP1Author affiliations:1St George’s University of London, UK2 National Amyloidosis Centre, Royal Free Campus, UCL, London, UKAddress for correspondence:Dr. Jason N DunguSt George’s University of LondonCranmer Terrace London SW17 0RE, UKFax number: +44 (0) 208 725 3328Telephone number: +44 (0) 208 725 5914Email address: j.dungu@Word count: 6901Subject codes: Race and ethnicity, cardiomyopathy, heart failure, echocardiography, mortality/survival ABSTRACTBackgroundIt has been reported that subjects of African descent present with heart failure at a younger age and due to different etiologies than Caucasians. We present contemporary data from UK Afro-Caribbean patients in London.Methods and ResultsAll heart failure patients presenting to St George’s Hospital Heart Failure clinic between 2005 and 2012 were included (n=1392). Patients were predominantly Caucasian (71%) and male (67%), median age at presentation73 years (range 18-100). In 211 Afro-Caribbean patients, the commonest cause of heart failure was non-ischemic dilated cardiomyopathy (DCM) in 27.5% (Caucasians 19.9%, p<0.001). Lower rates of ischemic cardiomyopathy (ICM) were observed (13% vs. 41%, p<0.001). The 4th commonest cause of heart failure in Afro-Caribbeans was cardiac amyloidosis (11.4%). The prevalence may have been even higher as not all patients were tested for amyloidosis. Patients with ATTR V122I had the worst prognosis compared to other causes of Afro-Caribbean heart failure and Caucasian patients. To better understand this condition, we analyzed data from the largest international cohort of ATTR V122I patients, followed at the UK National Amyloidosis Centre (n=72). Patients presented with cardiac failure (median age of 75, range 59-90 years). Median survival was 2.6 years from diagnosis. Conclusions In London, the etiology of heart failure varies depending on ethnicity and affects age of presentation and outcomes. In Afro-Caribbean patients, ATTR V122I is an underappreciated cause of heart failure, and cardiomyopathy is often misattributed to hypertension. As promising TTR therapies are in development, increased awareness and proactive detection is needed. Key words:Ethnicity, heart failure, amyloid, prognosisINTRODUCTIONMost large heart failure studies in the United Kingdom population fail to include specific data on Afro-Caribbean patients because ethnic minority groups form a relatively small proportion nationwide.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/hrt.2010.209171", "ISSN" : "1355-6037", "PMID" : "21173198", "abstract" : "Objectives To obtain national data on the clinical characteristics, investigation, management and outcome of patients hospitalised with a diagnosis of heart failure. Method A survey was carried out of the first 10 patients hospitalised with a primary diagnosis of heart failure each month in 86 hospitals providing services for acute medical admissions in England and Wales from April 2008 until March 2009. The main outcome measures were rates of investigations, treatments and specialist management, length of hospital stay and mortality. Results The 86 hospitals enrolled 6170 patients with a median age of 78&emsp14;years (IQR 70-85&emsp14;years), including 2639 (43%) women. At admission, only 30% of patients were breathless at rest, while 43% had peripheral oedema. Echocardiograms were recorded in 75% of patients and left ventricular ejection fraction (LVEF) was \u226440% in 78%. Natriuretic peptides were rarely measured. Allowing for missing data, >90% of patients were treated with loop diuretics at discharge, 80% with ACE inhibitors or angiotensin receptor blockers, 50% with \u03b2-blockers and 30% with aldosterone antagonists. Patients with an LVEF <40% were more likely to receive these agents. Median hospital stay was 9&emsp14;days (IQR 5-17) and in-patient mortality was 12%. Patients admitted to general medicine rather than cardiology wards were more likely to die (HR=2.5, 95% CI 2.0 to 3.3, p<0.001) even after adjusting for differences (HR=1.9, 95% CI 1.5 to 2.5, p<0.001). Projected 1-year mortality below and above age 75&emsp14;years was 26% and 56%, with higher rates if managed on general medicine rather than cardiology wards (HR=1.4, 95% CI 1.2 to 1.6, p<0.001). Conclusion The prognosis of patients hospitalised with heart failure remains poor and investigation and treatment suboptimal. Specialist services are associated with higher rates of investigation and treatment and improved outcome.", "author" : [ { "dropping-particle" : "", "family" : "Cleland", "given" : "John G F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McDonagh", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rigby", "given" : "Alan S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yassin", "given" : "Ashraf", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whittaker", "given" : "Tracy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dargie", "given" : "Henry J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Heart", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2011", "6", "1" ] ] }, "page" : "876-886", "title" : "The national heart failure audit for England and Wales 2008-2009", "type" : "article-journal", "volume" : "97" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹", "plainTextFormattedCitation" : "1", "previouslyFormattedCitation" : "[1]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }1 However, more than one million people of Afro-Caribbean ethnicity live in the Greater London area (2011 census data) forming a significant proportion of the city’s population (13.3%).ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Office for National Statistics (ONS)", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "title" : "Ethnicity and National Identity in England and Wales 2011", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²", "plainTextFormattedCitation" : "2", "previouslyFormattedCitation" : "[2]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }2 There are few studies focusing on ethnic differences in heart failure in UK populations. Previous studies in African American subjects suggest that heart failure is less likely to be due to coronary artery disease and frequently due to hypertensive heart disease.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.amjcard.2005.07.028", "ISSN" : "0002-9149", "PMID" : "16226931", "abstract" : "The demographics of the United States are changing, and in the next few decades there will no longer be a racial/ethnic majority population. Increased awareness of cardiovascular disease (CVD) in special populations is warranted as these populations increase. Heart failure carries a substantial burden on those affected, particularly African Americans, who have a disproportionate burden of heart disease. Current treatments for heart failure include angiotensin-converting enzyme inhibitors, beta-blockers, angiotensin II-receptor antagonists, and vasodilating agents. This review discusses the unique characteristics of CVD in African Americans and addresses the need for targeted treatments to reduce the excess burden found in this population.", "author" : [ { "dropping-particle" : "", "family" : "Yancy", "given" : "Clyde W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of cardiology", "id" : "ITEM-1", "issue" : "7B", "issued" : { "date-parts" : [ [ "2005", "10" ] ] }, "page" : "3i-12i", "title" : "Heart failure in African Americans.", "type" : "article-journal", "volume" : "96" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³", "plainTextFormattedCitation" : "3", "previouslyFormattedCitation" : "[3]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }3 The limited reports in the UK Afro-Caribbean population suggest this cohort often present in heart failure with preserved ejection fraction (HFpEF) which may be related to hypertensive cardiomyopathy.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0026710", "ISSN" : "1932-6203", "PMID" : "22110591", "abstract" : "BACKGROUND: Limited data exists on the prevalence of heart failure amongst minority groups in the UK. To document the community prevalence and severity of left ventricular systolic dysfunction, heart failure, and atrial fibrillation, amongst the South Asian and Black African-Caribbean groups in the UK.\n\nMETHODS AND RESULTS: We conducted a cross-sectional study recruiting from September 2006 to July 2009 from 20 primary care centres in Birmingham, UK. 10,902 eligible subjects invited, 5,408 participated (49.6%) and 5,354 had complete data (49.1%). Subjects had median age 58.2 years (interquartile range 51.0 to 70.0), and 2544 (47.5%) were male. Of these, 1933 (36.3%) had BMI>30 kg/m(2), 1,563 (29.2%) had diabetes, 2676 (50.0%) had hypertension, 307 (5.7%) had a history of myocardial infarction, and 104 (1.9%) had history of arrhythmia. Overall, 59 (1.1%) had an Ejection Fraction<40%, and of these 40 (0.75%) were NYHA class \u22652; 51 subjects (0.95%) had atrial fibrillation. Of the remaining 19 patients with an EF<40%, only 4 patients were treated with furosemide. A further 54 subjects had heart failure with preserved ejection fraction.\n\nCONCLUSIONS: This is the largest study of the prevalence of left ventricular systolic dysfunction, heart failure and atrial fibrillation in under-researched minority communities in the UK. The prevalence of heart failure in these minority communities appears comparable to that of the general population but less than anticipated given the high rates of cardiovascular disease in these groups. Heart failure continues to be a major cause of morbidity in all ethnic groups and preventive strategies need to be identified and implemented.", "author" : [ { "dropping-particle" : "", "family" : "Gill", "given" : "Paramjit S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Calvert", "given" : "Melanie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davis", "given" : "Russell", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "Michael K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freemantle", "given" : "Nick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lip", "given" : "Gregory Y H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2011", "1" ] ] }, "page" : "e26710", "title" : "Prevalence of heart failure and atrial fibrillation in minority ethnic subjects: the Ethnic-Echocardiographic Heart of England Screening Study (E-ECHOES).", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴", "plainTextFormattedCitation" : "4", "previouslyFormattedCitation" : "[4]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }4 The role of Afro-Caribbean ethnicity in cardiovascular risk is still not fully understood. A higher prevalence of hypertension, elevated body mass index (BMI) and diabetes is recognized.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0194-911X", "PMID" : "8319998", "abstract" : "To investigate why mortality from stroke in people of Afro-Caribbean origin is twice the average for England and Wales, we examined 1166 European and Afro-Caribbean people in London. Age-standardized median systolic blood pressure was 6 mm Hg higher (128 versus 122 mm Hg) in Afro-Caribbean than European men and 17 mm Hg higher (135 versus 118 mm Hg) in Afro-Caribbean than European women. Migrants from West Africa and the Caribbean had similar blood pressures. Body mass index was higher in Afro-Caribbean than European women, accounting for 4 mm Hg of the systolic difference. Diabetes prevalence was 16% in Afro-Caribbeans and 5% in Europeans (P < .001), accounting for 1 mm Hg of the difference in systolic pressure in men and 2 mm Hg in women. In participants not taking antihypertensive medication, mean fall in ambulatory systolic pressure between daytime and nighttime, adjusted for resting blood pressures, was 24 mm Hg in Europeans and 18 mm Hg in Afro-Caribbeans (P = .05), and percent day-night fall in systolic blood pressure adjusted for resting systolic pressure was 17% in Europeans and 12% in Afro-Caribbeans (P < .05). This difference persisted when men and women and normotensive and hypertensive individuals were examined separately. We estimate that the differences in blood pressure between Afro-Caribbeans and Europeans may be enough to account for ethnic differences in stroke mortality in women but not men. The reasons for the high prevalence of hypertension and related morbidity in this and other populations of African descent remain to be established.", "author" : [ { "dropping-particle" : "", "family" : "Chaturvedi", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McKeigue", "given" : "P M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marmot", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Hypertension", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1993", "7" ] ] }, "page" : "90-6", "title" : "Resting and ambulatory blood pressure differences in Afro-Caribbeans and Europeans.", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁵", "plainTextFormattedCitation" : "5", "previouslyFormattedCitation" : "[5]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }5 We have identified a rapidly progressive form of heart failure in elderly Afro-Caribbean patients in increasing numbers over recent years due to cardiac amyloidosis.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "doi:10.1136/heartjnl-2012-301924", "abstract" : "Cardiac amyloidosis of transthyretin fibril protein (ATTR) type is an infiltrative cardiomyopathy characterised by ventricular wall thickening and diastolic heart failure. Increased access to cardiovascular magnetic resonance imaging has led to a marked increase in referrals to our centre of Caucasian patients with wild-type ATTR (senile systemic) amyloidosis and Afro-Caribbean patients with the hereditary ATTR V122I type. Both subtypes present predominantly as isolated cardiomyopathy. The differential diagnosis includes cardiac amyloid light-chain (AL) amyloidosis, which has a poorer prognosis and can be amenable to chemotherapy. We review here the clinical features of cardiac ATTR amyloidosis and describe the diagnostic tests to determine ATTR type. Correct diagnosis is ever more crucial given that several novel therapies for ATTR amyloidosis are on the near horizon.", "author" : [ { "dropping-particle" : "", "family" : "Dungu", "given" : "Jason N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anderson", "given" : "Lisa J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Carol J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Heart", "id" : "ITEM-1", "issue" : "21", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "1546-1554", "title" : "Cardiac transthyretin amyloidosis", "type" : "article-journal", "volume" : "98" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶", "plainTextFormattedCitation" : "6", "previouslyFormattedCitation" : "[6]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6 Variant transthyretin V122I has been estimated to be carried by 3.43% of African Americans and is inherited in autosomal dominant fashion.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3109/13506129.2015.1051219", "ISSN" : "1744-2818", "PMID" : "26123279", "abstract" : "BACKGROUND: Transthyretin (TTR) V122I (rs76992529) is one of 111 variants caused by point mutations in the coding sequence of the human TTR gene that are associated with systemic amyloidosis. It results from a G to A transition at a CG dinucleotide in codon 142(122 of the mature protein) of the gene and has been described almost exclusively in people of African descent. Several series have reported allele frequencies from 0.015 to 0.020 in African-Americans. OBJECTIVE: To define more accurately the frequency of the TTR V122I variant allele in the African-American population. METHODS: DNA isolated from blood spots from 1688 New York State African-American newborns was genotyped for the TTR V122I allele. We also compiled new data from the Jackson Heart Study and previously unpublished data from the Dallas Heart Study, plus data from a San Diego \"wellness study\", providing 15 650 additional allelotypes to those already reported. RESULTS: Among the New York newborns, the TTR V122I allele was present in 65/3376 alleles (allele prevalence 0.0193). The combined available data from all the non-selected African-American cohorts showed the TTR variant allele to be present in 451/26 062 alleles (allele prevalence of 0.0173), slightly but not significantly lower than our previously published estimates. CONCLUSIONS: The allele prevalence for TTR V122I in African-Americans is 0.0173. Of African-Americans under age 65, 3.43% carry at least one copy of the variant amyloidogenic allele.", "author" : [ { "dropping-particle" : "", "family" : "Jacobson", "given" : "Daniel R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alexander", "given" : "Alice A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tagoe", "given" : "Clement", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buxbaum", "given" : "Joel N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "6", "30" ] ] }, "page" : "1-4", "title" : "Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷", "plainTextFormattedCitation" : "7", "previouslyFormattedCitation" : "[7]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }7 Transthyretin amyloidosis (ATTR) V122I is associated with isolated cardiac involvement in patients over the age of 60 years affecting males to females in a ratio of 6:1.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "doi:10.1136/heartjnl-2012-301924", "abstract" : "Cardiac amyloidosis of transthyretin fibril protein (ATTR) type is an infiltrative cardiomyopathy characterised by ventricular wall thickening and diastolic heart failure. Increased access to cardiovascular magnetic resonance imaging has led to a marked increase in referrals to our centre of Caucasian patients with wild-type ATTR (senile systemic) amyloidosis and Afro-Caribbean patients with the hereditary ATTR V122I type. Both subtypes present predominantly as isolated cardiomyopathy. The differential diagnosis includes cardiac amyloid light-chain (AL) amyloidosis, which has a poorer prognosis and can be amenable to chemotherapy. We review here the clinical features of cardiac ATTR amyloidosis and describe the diagnostic tests to determine ATTR type. Correct diagnosis is ever more crucial given that several novel therapies for ATTR amyloidosis are on the near horizon.", "author" : [ { "dropping-particle" : "", "family" : "Dungu", "given" : "Jason N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anderson", "given" : "Lisa J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Carol J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Heart", "id" : "ITEM-1", "issue" : "21", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "1546-1554", "title" : "Cardiac transthyretin amyloidosis", "type" : "article-journal", "volume" : "98" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶", "plainTextFormattedCitation" : "6", "previouslyFormattedCitation" : "[6]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6 Survival in ATTR V122I is reported to be poor ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1097-6744", "abstract" : "TRACS sought to describe the clinical outcomes and disease progression of transthyretin (TTR) cardiac amyloidosis (ATTR) in an observational study. Clinical course is largely determined by disease type with ATTR categorized as wild-type (ATTRwt) or genetic-variant protein (ATTRm). Prospective data are lacking in the most common TTR mutation, V122I, present in approximately 3.5% of African Americans.", "author" : [ { "dropping-particle" : "", "family" : "Ruberg", "given" : "Frederick L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maurer", "given" : "Mathew S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Judge", "given" : "Daniel P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zeldenrust", "given" : "Steven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Skinner", "given" : "Martha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Antony Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falk", "given" : "Rodney H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cheung", "given" : "Kin N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patel", "given" : "Ayan R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pano", "given" : "Arian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Packman", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grogan", "given" : "Donna Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American heart journal", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "8" ] ] }, "page" : "222-228.e1", "title" : "Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis Cardiac Study (TRACS).", "type" : "article-journal", "volume" : "164" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁸", "plainTextFormattedCitation" : "8", "previouslyFormattedCitation" : "[8]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }8 but the prevalence of the clinical phenotype in the British Afro-Caribbean population is unknown. The clinical features and natural history of ATTR V122I amyloidosis have been little studied. The Transthyretin Amyloidosis Cardiac Study (TRACS) reported only 11 patients with ATTR V122I subtype ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1097-6744", "abstract" : "TRACS sought to describe the clinical outcomes and disease progression of transthyretin (TTR) cardiac amyloidosis (ATTR) in an observational study. Clinical course is largely determined by disease type with ATTR categorized as wild-type (ATTRwt) or genetic-variant protein (ATTRm). Prospective data are lacking in the most common TTR mutation, V122I, present in approximately 3.5% of African Americans.", "author" : [ { "dropping-particle" : "", "family" : "Ruberg", "given" : "Frederick L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maurer", "given" : "Mathew S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Judge", "given" : "Daniel P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zeldenrust", "given" : "Steven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Skinner", "given" : "Martha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Antony Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falk", "given" : "Rodney H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cheung", "given" : "Kin N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patel", "given" : "Ayan R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pano", "given" : "Arian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Packman", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grogan", "given" : "Donna Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American heart journal", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "8" ] ] }, "page" : "222-228.e1", "title" : "Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis Cardiac Study (TRACS).", "type" : "article-journal", "volume" : "164" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁸", "plainTextFormattedCitation" : "8", "previouslyFormattedCitation" : "[8]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }8 and the Transthyretin Amyloidosis Outcomes Survey (THAOS), which is a multicenter, observational study that has reported 957 ATTR amyloidosis patients from 30 centers, included only 39 individuals with the V122I variant.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1185/03007995.2012.754348", "ISSN" : "1473-4877", "PMID" : "23193944", "abstract" : "Transthyretin (TTR) amyloidosis is a rare, life-threatening, systemic, autosomal dominant condition occurring in adults, with two main forms: hereditary (associated with TTR gene mutations) and wild-type. Studies indicate considerable heterogeneity in disease presentation, with predominantly polyneuropathic, predominantly cardiac, or mixed phenotypes.", "author" : [ { "dropping-particle" : "", "family" : "Coelho", "given" : "Teresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maurer", "given" : "Mathew S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suhr", "given" : "Ole B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current medical research and opinion", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "1" ] ] }, "page" : "63-76", "title" : "THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis.", "type" : "article-journal", "volume" : "29" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹", "plainTextFormattedCitation" : "9", "previouslyFormattedCitation" : "[9]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }9This study aims to: 1) compare and contrast clinical presentations and outcomes of heart failure patients depending on Caucasian or Afro-Caribbean ethnicity in the UK setting; 2) evaluate the prevalence of ATTR V122I as a cause of heart failure in Afro-Caribbean patients in London; and 3) describe the clinical phenotype of the disease for ATTR V122I patients with histologically proven amyloidosis. METHODSPatient identification in the general heart failure clinic (SGH)St George’s Hospital (SGH) is a regional cardiac center and local general hospital for a large catchment area of South West London of approximately 1.5 million people. All patients referred to the clinic with heart failure between September 2005 and November 2012 were eligible for inclusion in this analysis. Clinic patients were referred from local primary care clinicians following a suspected diagnosis of heart failure or by the medical teams following an in-patient admission with decompensated heart failure. The diagnosis was defined according to history and examination, echocardiographic findings and, when clinically indicated, supported by non-invasive ischemia testing, invasive cardiac catheterization in the setting of regional wall motion abnormalities, positive stress testing or angina, cardiovascular magnetic resonance (CMR), serology, genetic testing and endomyocardial biopsy if indicated. The etiologies listed are deemed the primary cause of heart failure symptoms and were determined at initial assessment and verified at the time of analysis following thorough review of patient records and any subsequent investigations or findings. Ischemic cardiomyopathy was diagnosed in the context of coronary artery disease and regional wall motion abnormalities on cardiac imaging or positive ischemia testing; dilated cardiomyopathy in the absence of obstructive coronary artery disease or known causes of ventricular dilatation; hypertensive heart disease in the context of documented systemic hypertension at presentation with left ventricular hypertrophy and no other cause for heart failure determined through cardiac imaging, with cardiac biopsy to rule out amyloidosis if diffuse late gadolinium enhancement on CMR was found. Patient ethnicity was determined via self-reported forms completed at the time of registration, according to Office of National Statistics (ONS) classifications. The term “Caucasian” has been used in reference to all white ethnicities and “Afro-Caribbean” for all black ethnicities. Prospective collection of data has been made over the years with corresponding census of survival. Completions were made by interrogating the Electronic Patient Records, namely updating mortality dates, latest hospital discharges, visits for imaging studies, or latest biochemistry results and cross confirmation with the NHS Strategic Tracing Service.Specialist referral clinic (NAC)In order to understand this condition further, we collaborated with the UK National Amyloidosis Centre (NAC) to describe the clinical phenotype, including patients identified at SGH. Only patients possessing the amyloidogenic gene mutation producing variant TTR V122I and a positive biopsy to confirm systemic amyloidosis were included in the analyses. Ethnicity was derived from self-reported questionnaires. Mortality data were obtained from the Office of National Statistics.InvestigationsLow voltage amplitude on ECG was defined as: mean limb lead (I, II, III, aVL, and aVF) QRS amplitude <0.5?mV; and sum of S wave in V1 and mean of the R wave in V5 and V6 <1.5?mV.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0002-9149", "PMID" : "6459025", "abstract" : "Fourteen patients with biopsy-proved systemic amyloidosis underwent noninvasive cardiac testing to assess the presence and severity of cardiac amyloidosis. There was a clear tendency for electrocardiographic voltage to be low (sum of S wave in lead V1 plus R wave in lead V5 or V6 [SV1 + RV5 or V6] = 14.6 +/- 4.8 mm; normal range 15 to 35) and echocardiographic muscle cross-sectional area to be increased (11.4 +/- 2.7 cm2/m2; normal range 6 to 10). When the electrocardiographic or the echocardiographic data were examined individually, and especially when they were compared and contrasted with similar measurements from patients with pericardial disease (n = 8) or aortic valve disease (n = 24), it was apparent that the electrocardiogram and the echocardiogram had limited specificity in the diagnosis of amyloidosis. However, when the analysis combined these two techniques, a distinctive pattern emerged. There was an inverse correlation between voltage and muscle cross-sectional area (r = -0.79) in patients with amyloidosis; moreover, marked derangement of the voltage/cross-sectional area relation was associated with clinical symptoms and mortality. In addition, patients with amyloidosis and cardiac symptoms had abnormal left ventricular chamber radius to wall thickness ratios, consistent with infiltration of the myocardium as the primary abnormality in cardiac amyloidosis.", "author" : [ { "dropping-particle" : "", "family" : "Carroll", "given" : "J D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gaasch", "given" : "W H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McAdam", "given" : "K P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of cardiology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1982", "1" ] ] }, "page" : "9-13", "title" : "Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation.", "type" : "article-journal", "volume" : "49" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰", "plainTextFormattedCitation" : "10", "previouslyFormattedCitation" : "[10]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }10 Cornell criteria ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0009-7322", "PMID" : "2949887", "abstract" : "In a previous study of 543 patients we developed, using echocardiographic left ventricular mass as the reference standard, two new sets of criteria that improve the electrocardiographic diagnosis of left ventricular hypertrophy (LVH). One set of criteria, which is suitable for routine clinical use, detects LVH when the sum of voltage in RaVL + SV3 (Cornell voltage) exceeds 2.8 mV in men and 2.0 mV in women. The second set of criteria, suitable for use in interpretation of the computerized electrocardiogram, uses logistic regression models based on electrocardiographic and demographic variables with independent predictive value for LVH, with separate equations for patients in sinus rhythm and atrial fibrillation. To test these criteria prospectively with use of a different reference standard, antemortem electrocardiograms were compared with left ventricular muscle mass measured at autopsy in 135 patients. Sensitivity of standard Sokolow-Lyon voltage (SLV) criteria (SV1 + RV5 or RV6 greater than 3.5 mV) for LVH was only 22%, but specificity was 100%. The Cornell voltage criteria improved sensitivity to 42%, while maintaining high specificity at 96%. Higher sensitivity (62%) was achieved by use of the new regression criteria, with a specificity of 92%. Overall test accuracy was 60% for SLV criteria, 68% for the Cornell voltage criteria, and 77% for the new regression criteria (p less than .005 vs SLV). We conclude that the Cornell voltage criteria improve the sensitivity of the electrocardiogram for detection of LVH and are easily applicable in clinical practice.(ABSTRACT TRUNCATED AT 250 WORDS)", "author" : [ { "dropping-particle" : "", "family" : "Casale", "given" : "P N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Devereux", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alonso", "given" : "D R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Campo", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kligfield", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Circulation", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1987", "3" ] ] }, "page" : "565-72", "title" : "Improved sex-specific criteria of left ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: validation with autopsy findings.", "type" : "article-journal", "volume" : "75" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹¹", "plainTextFormattedCitation" : "11", "previouslyFormattedCitation" : "[11]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }11 defined left ventricular hypertrophy (LVH), reported to have higher specificity in Afro-Caribbean patients.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jacc.2008.12.015", "ISSN" : "1558-3597", "PMID" : "19281932", "author" : [ { "dropping-particle" : "", "family" : "Hancock", "given" : "E William", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deal", "given" : "Barbara J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mirvis", "given" : "David M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Okin", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kligfield", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gettes", "given" : "Leonard S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bailey", "given" : "James J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Childers", "given" : "Rory", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gorgels", "given" : "Anton", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Josephson", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kors", "given" : "Jan a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Macfarlane", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mason", "given" : "Jay W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pahlm", "given" : "Olle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rautaharju", "given" : "Pentti M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Surawicz", "given" : "Borys", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Herpen", "given" : "Gerard", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wagner", "given" : "Galen S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wellens", "given" : "Hein", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American College of Cardiology", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2009", "3", "17" ] ] }, "page" : "992-1002", "publisher" : "American College of Cardiology Foundation", "title" : "AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scientific statement from the American Heart Association Electrocardiography", "type" : "article-journal", "volume" : "53" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹²", "plainTextFormattedCitation" : "12", "previouslyFormattedCitation" : "[12]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }12 Echocardiography was performed using a GE system (Vivid 7 since 2005). British Society of Echocardiography defined criteria for left and right ventricular (LV/RV) wall thickening and LV diastolic dysfunction were used. LV ejection fraction (EF) was assessed with biplane Simpson’s method.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.echo.2005.10.005", "ISSN" : "1097-6795", "PMID" : "16376782", "author" : [ { "dropping-particle" : "", "family" : "Lang", "given" : "Roberto M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bierig", "given" : "Michelle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Devereux", "given" : "Richard B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flachskampf", "given" : "Frank A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "Elyse", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pellikka", "given" : "Patricia A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Picard", "given" : "Michael H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roman", "given" : "Mary J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seward", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shanewise", "given" : "Jack S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Solomon", "given" : "Scott D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spencer", "given" : "Kirk T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sutton", "given" : "Martin St John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stewart", "given" : "William J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2005", "12" ] ] }, "page" : "1440-63", "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 Echocardiograph", "type" : "article-journal", "volume" : "18" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³", "plainTextFormattedCitation" : "13", "previouslyFormattedCitation" : "[13]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }13 LV mass was calculated with the corrected American Society of Echocardiography simplified cubed equation. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0002-9149", "PMID" : "2936235", "abstract" : "To determine the accuracy of echocardiographic left ventricular (LV) dimension and mass measurements for detection and quantification of LV hypertrophy, results of blindly read antemortem echocardiograms were compared with LV mass measurements made at necropsy in 55 patients. LV mass was calculated using M-mode LV measurements by Penn and American Society of Echocardiography (ASE) conventions and cube function and volume correction formulas in 52 patients. Penn-cube LV mass correlated closely with necropsy LV mass (r = 0.92, p less than 0.001) and overestimated it by only 6%; sensitivity in 18 patients with LV hypertrophy (necropsy LV mass more than 215 g) was 100% (18 of 18 patients) and specificity was 86% (29 of 34 patients). ASE-cube LV mass correlated similarly to necropsy LV mass (r = 0.90, p less than 0.001), but systematically overestimated it (by a mean of 25%); the overestimation could be corrected by the equation: LV mass = 0.80 (ASE-cube LV mass) + 0.6 g. Use of ASE measurements in the volume correction formula systematically underestimated necropsy LV mass (by a mean of 30%). In a subset of 9 patients, 3 of whom had technically inadequate M-mode echocardiograms, 2-dimensional echocardiographic (echo) LV mass by 2 methods was also significantly related to necropsy LV mass (r = 0.68, p less than 0.05 and r = 0.82, p less than 0.01). Among other indexes of LV anatomy, only measurement of myocardial cross-sectional area was acceptably accurate for quantitation of LV mass (r = 0.80, p less than 0.001) or diagnosis of LV hypertrophy (sensitivity = 72%, specificity = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)", "author" : [ { "dropping-particle" : "", "family" : "Devereux", "given" : "R B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alonso", "given" : "D R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lutas", "given" : "E M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gottlieb", "given" : "G J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Campo", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sachs", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reichek", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of cardiology", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1986", "2" ] ] }, "page" : "450-8", "title" : "Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings.", "type" : "article-journal", "volume" : "57" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴", "plainTextFormattedCitation" : "14", "previouslyFormattedCitation" : "[14]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }14Cardiovascular magnetic resonance (CMR) studies from referring centers were analyzed ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jcmg.2013.08.015", "ISSN" : "1876-7591", "PMID" : "24412186", "abstract" : "OBJECTIVES: This study was devised to describe the different cardiac magnetic resonance (CMR) appearances in light chain amyloid (AL) and transthyretin-related amyloidosis (ATTR). BACKGROUND: CMR is increasingly used to investigate patients with suspected amyloidosis. Global subendocardial late gadolinium enhancement (LGE) has been reported as typical of AL amyloidosis, whereas different patterns have been noted in ATTR amyloidosis. METHODS: We performed de novo analyses on original DICOM magnetic resonance imaging in 46 patients with cardiac AL amyloidosis and 51 patients with ATTR type who had been referred to a specialist amyloidosis center between 2007 and 2012 after CMR. Histological examination was performed in all cases, with immunohistochemistry, to confirm systemic amyloidosis. RESULTS: Patients' median age was 68 \u00b1 10 years, and 74% were male. Left ventricular mass was markedly increased in ATTR amyloidosis (228 g [202 to 267 g]) compared with AL type (167 g [137 to 191 g]) (p < 0.001). LGE was detected in all but 1 cardiac amyloidosis patient (AL type) and was substantially more extensive in ATTR compared with AL amyloidosis. Ninety percent of ATTR patients demonstrated transmural LGE compared with 37% of AL patients (p < 0.001). Right ventricular LGE was apparent in all ATTR patients but in only 33 AL patients (72%) (p < 0.001). Despite these findings, survival was significantly better in cardiac ATTR amyloidosis compared with AL type. We derived an LGE scoring system (Query Amyloid Late Enhancement) that independently differentiated ATTR from AL amyloidosis and, when incorporated into a logistic regression model with age and wall thickness, detected ATTR type with 87% sensitivity and 96% specificity. CONCLUSIONS: Transmural patterns of LGE distinguished ATTR from AL cardiac amyloidosis with high accuracy in this real-world analysis of CMR. Precise diagnosis of cardiac amyloidosis is crucial given the role of chemotherapy in AL type and with novel therapies for ATTR type currently in development.", "author" : [ { "dropping-particle" : "", "family" : "Dungu", "given" : "Jason N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valencia", "given" : "Oswaldo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pinney", "given" : "Jennifer H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gibbs", "given" : "Simon D J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rowczenio", "given" : "Dorota", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gilbertson", "given" : "Janet A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lachmann", "given" : "Helen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wechalekar", "given" : "Ashutosh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillmore", "given" : "Julian D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Carol J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anderson", "given" : "Lisa J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JACC. Cardiovascular imaging", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2014", "1", "2" ] ] }, "page" : "133-142", "title" : "CMR-Based Differentiation of AL and ATTR Cardiac Amyloidosis.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁵", "plainTextFormattedCitation" : "15", "previouslyFormattedCitation" : "[15]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }15 using dedicated software (CMRtools 2012, Cardiovascular Imaging Solutions, London) and reported according to international guidelines.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/1532-429X-11-5", "ISSN" : "1532-429X", "PMID" : "19257889", "abstract" : "These reporting guidelines are recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) to provide a framework for healthcare delivery systems to disseminate cardiac and vascular imaging findings related to the performance of cardiovascular magnetic resonance (CMR) examinations.", "author" : [ { "dropping-particle" : "", "family" : "Hundley", "given" : "W Gregory", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bluemke", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Jan G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Friedrich", "given" : "Matthias G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Higgins", "given" : "Charles B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lawson", "given" : "Mark A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "McConnell", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Raman", "given" : "Subha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossum", "given" : "Albert C", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flamm", "given" : "Scott", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kramer", "given" : "Christopher M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nagel", "given" : "Eike", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Neubauer", "given" : "Stefan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2009", "1" ] ] }, "page" : "5", "title" : "Society for Cardiovascular Magnetic Resonance guidelines for reporting cardiovascular magnetic resonance examinations.", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁶", "plainTextFormattedCitation" : "16", "previouslyFormattedCitation" : "[16]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }16 Gadolinium contrast was used in each CMR study. 99mTc-3,3-diphos- phono-1,2-propanodicarboxylic acid (DPD) scintigraphy was performed using two General Electric (GE) hybrid SPECT-CT gamma cameras (Infinia Hawkeye 4 and Discovery 670). Patients received 700 MBq 99mTc DPD, and planar whole body images were acquired after 3 hours, along with cardiac SPECT-CT. Myocardial uptake was allocated a Perugini score grade 0-3. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jacc.2005.05.073", "ISSN" : "1558-3597", "PMID" : "16168294", "abstract" : "We investigated the diagnostic accuracy of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy for differentiation of monoclonal immunoglobulin light-chain (AL) and transthyretin (TTR)-related cardiac amyloidosis.", "author" : [ { "dropping-particle" : "", "family" : "Perugini", "given" : "Enrica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guidalotti", "given" : "Pier Luigi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salvi", "given" : "Fabrizio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cooke", "given" : "Robin M T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pettinato", "given" : "Cinzia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riva", "given" : "Letizia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leone", "given" : "Ornella", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farsad", "given" : "Mohsen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ciliberti", "given" : "Paolo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bacchi-Reggiani", "given" : "Letizia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fallani", "given" : "Francesco", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Branzi", "given" : "Angelo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rapezzi", "given" : "Claudio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American College of Cardiology", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2005", "9", "20" ] ] }, "page" : "1076-84", "title" : "Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy.", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷", "plainTextFormattedCitation" : "17", "previouslyFormattedCitation" : "[17]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }17 All patients undergoing genetic testing received counseling before and after blood samples were taken. DNA was extracted from whole blood and the coding regions of the transthyretin gene were amplified by polymerase-chain-reaction assay; exons 2, 3 and 4 were sequenced.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0021-9150", "PMID" : "1793440", "abstract" : "We describe a rapid screening procedure to identify known DNA sequence changes in individuals diagnosed as having heterozygous familial hypercholesterolaemia (FH). The screening is made possible by combining a rapid DNA extraction protocol and small scale polymerase chain reaction DNA amplification, followed by oligonucleotide melting or restriction enzyme digestion. We have screened for two different mutations; firstly a mutation in the apolipoprotein B (apo B) gene that results in the substitution of glutamine (Gln) for arginine (Arg) at amino acid residue 3500 (apo B3500 mutation). Apo B is the principal component of the protein moiety of low density lipoprotein (LDL) and the mutation reduces the affinity for the LDL receptor (LDL-R). Secondly we have screened for a point mutation in the LDL-R gene itself that creates a new Pst I restriction enzyme site. This mutation in the LDL-R gene (LDL-R664 mutation) results in the substitution of leucine (Leu) for proline (Pro) at amino acid 664 and is known to slow processing of the LDL-R precursor to the mature form and to reduce the affinity of the receptor on the cell surface for LDL. In 77 unrelated patients with a clinical diagnosis of FH two out of 77 (2.6%) were positive for the apo B3500 mutation. Three (3.9%) were positive for the LDL-R664 mutation. Thus these two mutations might account for 5-6% of patients in the U.K. with a clinical diagnosis of FH (5000-6000 people).(ABSTRACT TRUNCATED AT 250 WORDS)", "author" : [ { "dropping-particle" : "", "family" : "Talmud", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tybjaerg-Hansen", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bhatnagar", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mbewu", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "J P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durrington", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Humphries", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Atherosclerosis", "id" : "ITEM-1", "issue" : "2-3", "issued" : { "date-parts" : [ [ "1991", "8" ] ] }, "page" : "137-41", "title" : "Rapid screening for specific mutations in patients with a clinical diagnosis of familial hypercholesterolaemia.", "type" : "article-journal", "volume" : "89" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0009-7322", "PMID" : "7850982", "abstract" : "BACKGROUND: Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal protein fibrils. Different proteins form the fibrils in different forms of the disease, and the condition can be acquired or hereditary. Involvement of the heart is quite common, producing a serious and usually fatal cardiomyopathy. Cardiac amyloidosis is often diagnosed late, and cardiac biopsy together with proper histological examination is essential. Contrary to previous perceptions, there is much recent evidence of effective treatment for several different types of systemic and cardiac amyloidosis, including the most common hereditary form caused by mutations in the transthyretin gene. Chemical and genetic typing of amyloid is therefore of considerable clinical importance. METHODS AND RESULTS: Seven members in two generations of an Italian family presented with cardiac disease inherited as an autosomal dominant and were found to have systemic amyloidosis. Angina pectoris-like pain, an unusual feature in cardiac amyloidosis, was a prominent symptom, possibly related to partial obliteration of the distal coronary arteries by amyloid infiltration. There were also cases of sudden cardiac death. Peripheral and autonomic neuropathy, which are the usual features of hereditary amyloidosis, were present in only two cases, and a diagnosis of acquired, immunoglobulin light chain (AL type) amyloidosis was suspected in the index case before the family history emerged. In fact, the amyloid fibrils were composed of transthyretin, and the two affected individuals from whom DNA was available were both heterozygotes for a single base change in exon 3 of the transthyretin gene, encoding substitution of Lys for the wild-type Thr residue at position 59 in the mature protein. This mutation has not previously been reported. CONCLUSIONS: We have identified a novel mutation in the transthyretin gene encoding 59Thr-->Lys associated with autosomal dominant hereditary systemic amyloidosis in an Italian kindred in whom cardiac involvement was the major feature. This family illustrates the difficulty in diagnosis of cardiac amyloid, the variable clinical phenotype in hereditary amyloidosis even within a family, and the importance of precise fibril typing for correct management in this condition.", "author" : [ { "dropping-particle" : "", "family" : "Booth", "given" : "D R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "S Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "P N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pepys", "given" : "M B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frustaci", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Circulation", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "1995", "2" ] ] }, "page" : "962-7", "title" : "A novel variant of transthyretin, 59Thr-->Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family.", "type" : "article-journal", "volume" : "91" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^18,19", "plainTextFormattedCitation" : "18,19", "previouslyFormattedCitation" : "[18,19]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }18,19 The presence of amyloid was confirmed by staining with Congo red and apple-green birefringence in cross-polarized light.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Puchtler", "given" : "H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sweat", "given" : "F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levine", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Histochemistry and Cytochemistry", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1962" ] ] }, "page" : "355", "publisher" : "Histochemical Soc", "title" : "On the binding of Congo red by amyloid", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁰", "plainTextFormattedCitation" : "20", "previouslyFormattedCitation" : "[20]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }20 Immunohistochemical staining was subsequently performed using the peroxidase anti-peroxidase method to confirm amyloid fibril type, using monospecific antibodies reactive with serum amyloid A protein (SAA), transthyretin (TTR) and kappa and lambda immunoglobulin light chains.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0076-6879", "PMID" : "10507014", "abstract" : "Two simple protocols are described for the isolation of amyloid fibrils that consist of water extraction from homogenates of unfixed, frozen human amyloidotic tissues. Most of the contaminating plasma and fibril-associated proteins are removed to yield relatively pure amyloid fibrils, suitable for biochemical characterization, functional assays, and biophysical studies of their structure using many of the specialized techniques described elsewhere throughout this volume.", "author" : [ { "dropping-particle" : "", "family" : "Tennent", "given" : "G A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Methods in enzymology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1999", "1" ] ] }, "page" : "26-47", "title" : "Isolation and characterization of amyloid fibrils from tissue.", "type" : "article-journal", "volume" : "309" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²¹", "plainTextFormattedCitation" : "21", "previouslyFormattedCitation" : "[21]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }21StatisticsStatistical analysis was performed using SPSS 21. Normally distributed data are presented as mean ± 1 standard deviation (SD). Non-normally distributed data are presented as median (25th and 75th percentiles). Categorical data are presented as frequencies and percentages. Dichotomous and categorical data for compared using Chi-square Test or Fisher's Exact Test; with calculation of odds ratios when appropriate. The distribution of continuous variables was assessed for normality with Shapiro-Wilk Test or W-statistic and groups were compared using the Independent Samples T Test for normally distributed data and Mann-Whitney or Wilcoxon tests for non- normally distributed data. We used Kaplan-Meier survival analysis to compare survival between Afro-Caribbean and Caucasian patients, then the impact of diagnosis on long-term survival among Afro-Caribbean patients only. We used the Gehan-Breslow test to compare curves and the Holm-Sidak method to account for multiple comparisons. Data regarding NYHA class was missing for some SGH patients and thus analysis was performed on 968 Caucasian and 197 Afro-Caribbean patients. The study was approved by the Ethics Committee of the Royal Free Hospital.RESULTSHeart failure was confirmed in 1392 patients in the heart failure clinic at SGH during the 7-year study period. The median age at presentation was 73 years (range 18-100) with Caucasian (71%) and male (67%) predominance. Asian patients (14%) were predominantly of South Asian origin (originating from India, Pakistan, and Bangladesh); we have excluded these patients from subsequent analyses for clarity. A total of 211 Afro-Caribbean patients (15%), 68 female and 143 male, presented during this time period - Black Caribbean 118 (55%); Black African 88 (41%); Mixed black and white ethnicity 9 (4%). Afro-Caribbean patients were significantly younger (71 years, 25th - 75th percentiles 54-77) than Caucasians (74 years, 25th - 75th percentiles 64-82, p<0.001) with a smaller proportion presenting aged 80 years and over (19% vs. 33%, p<0.001). Black Caribbean patients (median 73 years, 25th - 75th percentiles 58-78) were significantly older than Black African patients (median 65 years, 25th - 75th percentiles 47-74, p = 0.007). Hypertension was significantly more prevalent in Afro-Caribbean patients (71% vs. 54% in Caucasians, p < 0.001). History of cerebrovascular accident (CVA) was similar in Caucasian and Afro-Caribbean patients (13% vs. 14%, p = 0.69). Investigation rates differed in Afro-Caribbean patients, with higher rates of CMR (41% vs. 21% for Caucasian patients, p <0.001) and cardiac biopsy (14% vs. 3% for Caucasian patients, p<0.001). Coronary intervention and biventricular pacemaker implantation (CRT) were performed less frequently in Afro-Caribbean patients, compared to Caucasian patients (8% vs. 20%, p < 0.001 and 26% vs. 17%, p = 0.006 respectively). Etiology of heart failureTable 1 compares Afro-Caribbean and Caucasian patients with both heart failure and preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction. A total of 352 Caucasian patients had heart failure with ejection fraction ≥50% (36%) compared to 77 Afro-Caribbean patients (36%, p = 0.97). Overall ejection fraction was no different between groups (both 40%, p = 0.93). No significant difference in the presence of poor LV systolic function <35% was demonstrated between the 2 groups (Caucasian patients 32% vs. Afro-Caribbean patients 38%, p = 0.60). Left ventricular (LV) wall thickness was significantly higher in Afro-Caribbean patients (p<0.001). Ischemic cardiomyopathy was much less common in Afro-Caribbean patients (13%) than Caucasians (41%, p < 0.001). No difference in NT-prohormone brain natriuretic peptide (NT-pro BNP) was observed between groups (Caucasian patients 2459 ng/L (848-6525) vs. Afro-Caribbean patients 2195 ng/L (654-5132), p = 0.17). Atrial fibrillation was significantly more prevalent in Caucasian than Afro-Caribbean patients (35.8% vs. 21.3%, p<0.001).The top 5 diagnoses in Afro-Caribbean heart failure patients were: 1) Non-ischemic dilated cardiomyopathy (27%); 2) Ischemic heart disease (13%); 3) Hypertensive cardiomyopathy (12%); 4) cardiac amyloidosis (all subtypes - 11%); and 5) valvular heart disease (7%) – Supplementary Table 1. Cardiac amyloidosis secondary to variant ATTR V122I was diagnosed in 18 of 211 Afro-Caribbean patients (8.5%). All 18 patients with ATTR V122I were aged over 65 years (range 68-84), in keeping with the reported age-related clinical phenotype.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ahj.2009.08.006", "ISSN" : "1097-6744", "abstract" : "Background Transthyretin (TTR) mutations known to cause cardiac amyloidosis include V122I, found almost exclusively in African Americans at a prevalence of 3-3.9%. This retrospective study describes TTR V122I\u2013associated cardiac amyloid disease (ATTR) in a major amyloid referral clinic population. Methods Self-identified African Americans with amyloidosis (n = 156) were screened for TTR V122I by serum isoelectric focusing; mutant TTR was confirmed by DNA sequencing or mass spectrometry. Cardiac findings in ATTR V122I and immunoglobulin light chain (AL) amyloidoses were compared. Results TTR V122I was identified in 36/156 (23.1%) of evaluated patients and included 5 homozygotes; the allele frequency was 0.013. One compound heterozygote (F44L/V122I) and 4 patients who had AL and the mutant TTR allele were characterized. In patients negative for V122I, AL was the most frequent diagnosis (86/120). Cardiomyopathy was present in 100% of patients with ATTR and 84% of patients with AL (P = .01). In patients with dominant cardiac involvement, better survival occurred in ATTR (n = 30) compared to AL (n = 31), (27 vs 5 months, P b .01) although the mean age in ATTR was higher (70.3 vs 56.2 years, P b .01). Congestive heart failure symptoms and electrocardiographic findings were similar in ATTR and AL, but significant differences in echocardiographic measurements were observed. Conclusions ATTR V122I and AL are equally prevalent as the cause of cardiomyopathy in African Americans referred for a diagnosis of amyloidosis. Available therapy for AL underscores the need for early and accurate determination of amyloid type.", "author" : [ { "dropping-particle" : "", "family" : "Connors", "given" : "LH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prokaeva", "given" : "Tatiana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lim", "given" : "Amareth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Th\u00e9berge", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falk", "given" : "R.H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Doros", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berg", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Costello", "given" : "C.E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Hara", "given" : "C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seldin", "given" : "D.C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Skinner", "given" : "Martha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American heart journal", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "607-614", "title" : "Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis.", "type" : "article-journal", "volume" : "158" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²²", "plainTextFormattedCitation" : "22", "previouslyFormattedCitation" : "[22]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }22 Subgroup analysis revealed that 153 Afro-Caribbean patients aged over 60 years were referred to the heart failure clinic during the study period. The prevalence of ATTR V122I in Afro-Caribbean patients aged >60 years was 11.8%. The only other ATTR subtype diagnosed in Afro-Caribbean patients was non-hereditary senile cardiac amyloidosis due to wild-type TTR (4 patients, 1.9%). AL amyloidosis was diagnosed in only 2 Afro-Caribbean patients (0.95%). Of note, for all ethnicities, ATTR amyloidosis was found more frequently than AL type, an opposite finding to all other previous reports from specialist amyloidosis centers. Heart failure admissionsPatients were followed up in the general heart failure clinic for a median of 2.9 years (Caucasian patients 2.9 years, 25th - 75th percentiles 1-5, Afro-Caribbean patients 3.2 years, 25th - 75th percentiles 2-6, p = 0.02). During the follow-up period, the median hospitalization rate of all causes during follow-up in both Caucasian and Afro-Caribbean heart failure patients was 2 (range 0-64, 25th - 75th percentiles 0 - 4 vs. 0 - 5 respectively, p = 0.069). SurvivalSurvival differed significantly according to etiology and ethnicity overall (median survival in Caucasian 4.7 years vs. Afro-Caribbean 5.9 years, p = 0.031). 579 deaths occurred during follow up (486 Caucasians and 93 Afro-Caribbeans). No significant difference in survival was observed according to ethnicity in patients with ischemic cardiomyopathy (p = 0.25) or dilated cardiomyopathy (p = 0.71). Kaplan-Meier survival curves for the top 5 diagnoses in Afro-Caribbean heart failure patients are presented in Figure 1. No significant difference in median survival was observed between Afro-Caribbean patients with non-ischemic dilated cardiomyopathy and hypertensive cardiomyopathy (DCM 7.41 years, HTCM 7.32 years, p = 0.88) and patients with ATTR V122I had the poorest survival (ATTR V122I 2.33 years vs. DCM p<0.001 and vs. HTCM p=0.002). No significant difference in survival was observed between ATTR V122I and ICM (p = 0.11) or VHD (p = 0.19) in Afro-Caribbean patients. It should be noted that the age at presentation differed according to etiology. Afro-Caribbean patients with ATTR V122I presented at a relatively old age - median 76 years, interquartile range 74-78 – compared to Afro-Caribbean patients with DCM (68 years, 25th - 75th percentiles 51-75, p = 0.001) and HTCM (61 years, 25th - 75th percentiles 47-72, p = 0.001). The median age of Afro-Caribbean patients with ICM (76 years, 25th - 75th percentiles 71-81, p = 0.74) and valvular heart disease (81 years, 25th - 75th percentiles 74-85, p = 0.23) was similar to ATTR V122I. The median age of presentation was similar in Caucasians for each of these etiologies (67 years for DCM, p = 0.27; 82 years for VHD, p=0.54; and 75 years for ICM), except HTCM (79 years, p < 0.001).The clinical features of biopsy-proven ATTR V122I amyloidosisA total of 72 ATTR V122I patients with histological corroboration were reviewed at the UK National Amyloidosis Centre between January 1995 and March 2013, including the 18 SGH patients (Table 2). Cardiac biopsies were obtained in 39 patients (54%) and non-cardiac biopsies in 33 patients (46%, rectum n=12, fat pad n=10, stomach n=4, bone marrow n=3, prostate n=2, liver n=1 and carpal tunnel n=1). The median age at presentation was 74 years (range 59-90, 25th - 75th percentiles 70-80). Male predominance was observed (84.7%). The majority (85%) were referred from London centers. Black African or Caribbean ancestry was declared in 89%, including 2 patients of mixed ethnicity. The cohort included 8 patients of white ethnicity (8%), 1 Asian patient and 1 patient of Arabic descent. With regards to country of origin, 47% originated from Jamaica 18% from Nigeria, 15% from Ghana and less than 20% from other countries.Sixty-eight patients were heterozygous for the TTR V122I allele and 4 patients were homozygotes. All homozygous patients were male and presented at a younger age (65 ± 3 years) compared to heterozygotes (74 ± 7 years, p = 0.004). The majority of V122I ATTR patients were in New York Heart Failure Association (NYHA) class II and III (92%) at first review. Almost half (46%) had a history of carpal tunnel syndrome. A history of hypertension was common (47%). Median duration of symptoms prior to referral was 1.06 years (25th - 75th percentiles 0.68-2.41). Fluid overload was present in 60% of patients despite diuretic therapy. None of the patients exhibited macroglossia or peripheral neuropathy.Median serum Creatinine was 131 (25th - 75th percentiles 113-164) ?mol/L and glomerular filtration rate (GFR) was 48 (25th - 75th percentiles 39-61) ml/min. Renal impairment (estimated GFR <60 ml/min, corrected for ethnicity) was present in 79.4%. NT-pro brain natriuretic peptide (NT-pro BNP) was >100 pMol/L in 96% (median 435 pMol/L; 25th - 75th percentiles 269-644).ECG showed low voltage complexes in 38% and 17% had criteria for LVH (Table 3). Concentric LV wall thickening (>12mm) was evident on echocardiography in all patients, (median 17mm, 25th - 75th percentiles 15-19 vs. 17mm, 25th - 75th percentiles 16-18, p = 0.47). Diastolic dysfunction was present in every case, and was categorized as severe (grade 3 or 4) in 43%. LV ejection fraction was moderately impaired overall (mean 39 ± 11 %, range 19-69%). A small (<1.5cm) pericardial effusion was evident in 49% (Table 3). Thirty-nine patients (54%) underwent cardiovascular magnetic resonance (CMR) prior to referral. Mean LV end diastolic volume 140 ± 36 ml, mean LV end systolic volume 75 ± 33 ml and mean LV stroke volume 66 ± 19 ml. Mean LV ejection fraction 48 ± 14 %. Mean LV mass 230 g (25th - 75th percentiles 214-248) was hugely increased (mean 144 g and upper limit of normal 183 g for males aged >70 years). Extensive late gadolinium enhancement (LGE) was present in all. 99mTc-DPD scintigraphy was acquired in 27 patients (38%). All DPD scans were strongly positive with Perugini Grade 2 myocardial uptake in 15 patients (56%) and Grade 3 in 12 patients (44%).Survival in ATTR V122I During the follow-up period, 38 patients died (52.8%). Median (range) age at death was 77 years (64-91). The median survival from the date of diagnosis was 2.62 years. Median survival in Afro-Caribbean patients was 2.92 years compared to 1.45 years in Caucasian ATTR V122I patients. Of the 24 patients in whom mode of death details were available, 2 (8%) had a sudden cardiac death (neither had a pacing device and both died in their sleep), one patient died from a CVA after the implanted ICD converted previously undetected atrial fibrillation with fast ventricular rate to sinus rhythm and the rest (88%) died of progressive heart failure. No significant difference in survival was observed between NAC and SGH ATTR V122I patients (p = 0.36).DISCUSSIONWe report a study of Afro-Caribbean heart failure patients attending a general cardiology clinic and a description of the clinical phenotype for an important, as yet underappreciated, cause of heart failure ATTR V122I amyloidosis.Afro-Caribbean patients are frequently diagnosed with hypertensive heart failure and our data confirm that hypertensive cardiomyopathy is a relatively common cause of morbidity in this cohort (12%). Despite normal blood pressure at presentation, hypertension may be the etiology for many more of the non-ischemic dilated cardiomyopathy cohort, as 63% had a history of hypertension and many more had no regular BP checks prior to presentation. Survival in hypertensive cardiomyopathy and non-ischemic dilated cardiomyopathy was better than other causes of heart failure in Afro-Caribbean patients but the age at presentation for these diagnoses was significantly lower. Although heart failure seems different between races, when we compared heart failure by etiology the differences disappeared; once a patient has heart failure secondary to ischemic or dilated cardiomyopathy the survival is very similar regardless of ethnicity. Etiology also has an influence on apparent differences in the age of heart failure patients according to ethnicity. Age at presentation will contribute to poor survival in cardiac amyloidosis whereas hypertensive Afro-Caribbean patients present at a young age, from the age of 30 years.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ajh.2011.160", "ISSN" : "1941-7225", "PMID" : "21881618", "abstract" : "BACKGROUND: We assessed when blood pressure (BP) and hypertension begin to rise in African-Caribbeans compared to the white population; and whether the change relates to body mass index (BMI). METHODS: Secondary analysis of the cross-sectional Health Surveys for England among 22,723 participants (21,344 whites and 1,379 African-Caribbeans) adults aged \u226518 years. RESULTS: The cubic spline graphs showed a crossover (African-Caribbean greater than whites) at 30-40 years in BP. Age-specific mean BP and hypertension prevalence data showed at 20-29 years African-Caribbean men were advantaged but not thereafter. There was little difference in BMI in men. African-Caribbean women had lower systolic BP (but higher prevalence of hypertension) at 20-29 years but higher BP and prevalence of hypertension thereafter. African-Caribbean women had higher BMI than white women. Regression showed an age and ethnicity interaction for systolic (0.076 mm Hg greater increase per year, P = 0.054) and diastolic BP (0.068 mm Hg greater increase per year (P = 0.009) and hypertension (OR equals 1.02, P = 0.004) in African-Caribbean men, and diastolic BP in African-Caribbean women (0.057 mm Hg greater increase per year, P = 0.017). Crossover was 28, 44, and 28 years for systolic BP, diastolic BP and hypertension in men, respectively; and 40 years for diastolic BP in women. CONCLUSIONS: Clinicians should be extra vigilant about screening African-Caribbean patients from the age of 30 years. Detailed study is needed to understand the still mysterious mechanisms for this crossover.", "author" : [ { "dropping-particle" : "", "family" : "Agyemang", "given" : "Charles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Humphry", "given" : "Roger W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bhopal", "given" : "Raj", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of hypertension", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "89-96", "title" : "Divergence with age in blood pressure in African-Caribbean and white populations in England: implications for screening for hypertension.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²³", "plainTextFormattedCitation" : "23", "previouslyFormattedCitation" : "[23]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }23 Afro-Caribbean heart failure patients with hypertensive cardiomyopathy presented at a median 61 years of age in this study, significantly lowering the overall Afro-Caribbean heart failure age. Afro-Caribbean patients with hypertensive cardiomyopathy also presented significantly younger than Caucasians, reinforcing the need to treat a condition prevalent in this ethnic group aggressively.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/sj.jhh.1001586", "ISSN" : "0950-9240", "PMID" : "12874609", "abstract" : "The aim of the study was to review published evidence on whether blood pressure (BP) levels and the prevalence of hypertension are higher in adult populations of African descent living in the UK as compared to the white population. A systematic literature review was carried out using MEDLINE 1966-2002 and EMBASE 1980-2002 and citations from references. In all, 14 studies were identified. Nearly all studies were carried out in the London area. The data showed important differences between studies in terms of age and sex of samples, definition of African/black and methods of evaluating BP. A total of 10 studies reported higher mean systolic BPs, while 11 studies reported higher mean diastolic BPs in men from African descent compared to white men. In women, 10 of 12 studies reported higher systolic, and 10 of 12 studies reported higher diastolic BPs. For prevalence of hypertension, eight of 10 studies reported higher rates in men from African descent; eight of nine studies showed higher rates of hypertension in women from African descent. Overall, the most representative sample and up-to-date data came from the Health Survey for England '99. Ethnic group differences in BP were not present in the younger age groups. Women of African descent had higher BP and higher body mass index (BMI). In men of African descent high BP did not coincide with higher BMI. In conclusion, the reported higher rates of hypertension in people from African descent in the UK are confirmatory of the USA African-American and white comparisons. Variations in study methods, size and body composition, and in the mix of Afro-Caribbean and West African groups explain much of the inconsistent results in the UK studies.", "author" : [ { "dropping-particle" : "", "family" : "Agyemang", "given" : "Charles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bhopal", "given" : "Raj", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of human hypertension", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2003", "8" ] ] }, "page" : "523-34", "title" : "Is the blood pressure of people from African origin adults in the UK higher or lower than that in European origin white people? A review of cross-sectional data.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁴", "plainTextFormattedCitation" : "24", "previouslyFormattedCitation" : "[24]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }24 The high prevalence of cardiac amyloidosis and specifically the transthyretin subtype is striking. Cardiac ATTR V122I amyloidosis was a relatively common cause of heart failure in Afro-Caribbean patients presenting to the general heart failure clinic. The typical clinical picture in ATTR V122I amyloidosis is presentation with heart failure symptoms in the seventh decade and beyond, with fluid overload despite use of diuretics. The prognosis is poor, with a median survival of 2.6 years after confirmation of diagnosis. Survival compares poorly to other causes of heart failure in UK Afro-Caribbeans. Cardiac investigations revealed elevated serum biomarkers, increased LV wall thickness and impaired systolic and diastolic function. Almost half of patients had a history of carpal tunnel syndrome, which should be considered a red flag for this disease among older Afro-Caribbean heart failure patients. Despite autosomal dominant inheritance of the genetic variant, there was significant male predominance (85%). As we reported previously, the ECG may be misleading.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ahj.2012.04.013", "abstract" : "About 4% of African Americans possess the isoleucine 122 (V122I) variant of transthyretin, associated with cardiac amyloidosis beyond ages of 55 to 60 years. Transthyretin amyloidosis associated with variant V122I (ATTR V122I) is likely to be an important cause of heart failure in Afro-Caribbean populations, but the high prevalence of left ventricular hypertrophy (LVH) and lack of awareness of this genetic disorder pose diagnostic hurdles. We report the electrocardiographic (ECG) features of ATTR V122I in the largest clinical series to date.", "author" : [ { "dropping-particle" : "", "family" : "Dungu", "given" : "Jason", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sattianayagam", "given" : "Prayman T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Carol J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gibbs", "given" : "Simon D J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pinney", "given" : "Jennifer H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Banypersad", "given" : "Sanjay M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rowczenio", "given" : "Dorota", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gilbertson", "given" : "Janet A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lachmann", "given" : "Helen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wechalekar", "given" : "Ashutosh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillmore", "given" : "Julian D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anderson", "given" : "Lisa J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American heart journal", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "72-9", "title" : "The electrocardiographic features associated with cardiac amyloidosis of variant transthyretin Isoleucine 122 (V122I) type in Afro-Caribbean patients.", "type" : "article-journal", "volume" : "164" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁵", "plainTextFormattedCitation" : "25", "previouslyFormattedCitation" : "[25]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }25 Nearly one-fifth of patients had voltage criteria for LVH that is liable to be interpreted as an indication of hypertensive cardiomyopathy in the Afro-Caribbean population. CMR with gadolinium enhancement is more sensitive than echocardiography for identifying ATTR amyloidosis, as increased wall thickness and diastolic impairment are also found in hypertensive cardiomyopathy. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "doi:10.1136/heartjnl-2012-301924", "abstract" : "Cardiac amyloidosis of transthyretin fibril protein (ATTR) type is an infiltrative cardiomyopathy characterised by ventricular wall thickening and diastolic heart failure. Increased access to cardiovascular magnetic resonance imaging has led to a marked increase in referrals to our centre of Caucasian patients with wild-type ATTR (senile systemic) amyloidosis and Afro-Caribbean patients with the hereditary ATTR V122I type. Both subtypes present predominantly as isolated cardiomyopathy. The differential diagnosis includes cardiac amyloid light-chain (AL) amyloidosis, which has a poorer prognosis and can be amenable to chemotherapy. We review here the clinical features of cardiac ATTR amyloidosis and describe the diagnostic tests to determine ATTR type. Correct diagnosis is ever more crucial given that several novel therapies for ATTR amyloidosis are on the near horizon.", "author" : [ { "dropping-particle" : "", "family" : "Dungu", "given" : "Jason N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anderson", "given" : "Lisa J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Carol J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Heart", "id" : "ITEM-1", "issue" : "21", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "1546-1554", "title" : "Cardiac transthyretin amyloidosis", "type" : "article-journal", "volume" : "98" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.jcmg.2013.08.015", "ISSN" : "1876-7591", "PMID" : "24412186", "abstract" : "OBJECTIVES: This study was devised to describe the different cardiac magnetic resonance (CMR) appearances in light chain amyloid (AL) and transthyretin-related amyloidosis (ATTR). BACKGROUND: CMR is increasingly used to investigate patients with suspected amyloidosis. Global subendocardial late gadolinium enhancement (LGE) has been reported as typical of AL amyloidosis, whereas different patterns have been noted in ATTR amyloidosis. METHODS: We performed de novo analyses on original DICOM magnetic resonance imaging in 46 patients with cardiac AL amyloidosis and 51 patients with ATTR type who had been referred to a specialist amyloidosis center between 2007 and 2012 after CMR. Histological examination was performed in all cases, with immunohistochemistry, to confirm systemic amyloidosis. RESULTS: Patients' median age was 68 \u00b1 10 years, and 74% were male. Left ventricular mass was markedly increased in ATTR amyloidosis (228 g [202 to 267 g]) compared with AL type (167 g [137 to 191 g]) (p < 0.001). LGE was detected in all but 1 cardiac amyloidosis patient (AL type) and was substantially more extensive in ATTR compared with AL amyloidosis. Ninety percent of ATTR patients demonstrated transmural LGE compared with 37% of AL patients (p < 0.001). Right ventricular LGE was apparent in all ATTR patients but in only 33 AL patients (72%) (p < 0.001). Despite these findings, survival was significantly better in cardiac ATTR amyloidosis compared with AL type. We derived an LGE scoring system (Query Amyloid Late Enhancement) that independently differentiated ATTR from AL amyloidosis and, when incorporated into a logistic regression model with age and wall thickness, detected ATTR type with 87% sensitivity and 96% specificity. CONCLUSIONS: Transmural patterns of LGE distinguished ATTR from AL cardiac amyloidosis with high accuracy in this real-world analysis of CMR. Precise diagnosis of cardiac amyloidosis is crucial given the role of chemotherapy in AL type and with novel therapies for ATTR type currently in development.", "author" : [ { "dropping-particle" : "", "family" : "Dungu", "given" : "Jason N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Valencia", "given" : "Oswaldo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pinney", "given" : "Jennifer H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gibbs", "given" : "Simon D J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rowczenio", "given" : "Dorota", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gilbertson", "given" : "Janet A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lachmann", "given" : "Helen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wechalekar", "given" : "Ashutosh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillmore", "given" : "Julian D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Carol J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anderson", "given" : "Lisa J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "JACC. Cardiovascular imaging", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2014", "1", "2" ] ] }, "page" : "133-142", "title" : "CMR-Based Differentiation of AL and ATTR Cardiac Amyloidosis.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^6,15", "plainTextFormattedCitation" : "6,15", "previouslyFormattedCitation" : "[6,15]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6,15The allele frequency of ATTR V122I, an autosomal dominant condition, has been reported to be carried by 3.4% in African-Americans ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3109/13506129.2015.1051219", "ISSN" : "1744-2818", "PMID" : "26123279", "abstract" : "BACKGROUND: Transthyretin (TTR) V122I (rs76992529) is one of 111 variants caused by point mutations in the coding sequence of the human TTR gene that are associated with systemic amyloidosis. It results from a G to A transition at a CG dinucleotide in codon 142(122 of the mature protein) of the gene and has been described almost exclusively in people of African descent. Several series have reported allele frequencies from 0.015 to 0.020 in African-Americans. OBJECTIVE: To define more accurately the frequency of the TTR V122I variant allele in the African-American population. METHODS: DNA isolated from blood spots from 1688 New York State African-American newborns was genotyped for the TTR V122I allele. We also compiled new data from the Jackson Heart Study and previously unpublished data from the Dallas Heart Study, plus data from a San Diego \"wellness study\", providing 15 650 additional allelotypes to those already reported. RESULTS: Among the New York newborns, the TTR V122I allele was present in 65/3376 alleles (allele prevalence 0.0193). The combined available data from all the non-selected African-American cohorts showed the TTR variant allele to be present in 451/26 062 alleles (allele prevalence of 0.0173), slightly but not significantly lower than our previously published estimates. CONCLUSIONS: The allele prevalence for TTR V122I in African-Americans is 0.0173. Of African-Americans under age 65, 3.43% carry at least one copy of the variant amyloidogenic allele.", "author" : [ { "dropping-particle" : "", "family" : "Jacobson", "given" : "Daniel R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alexander", "given" : "Alice A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tagoe", "given" : "Clement", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buxbaum", "given" : "Joel N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015", "6", "30" ] ] }, "page" : "1-4", "title" : "Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷", "plainTextFormattedCitation" : "7", "previouslyFormattedCitation" : "[7]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }7 but the gene frequency in the UK population is unknown. The penetrance of TTR gene mutations is also unknown but reported to be variable. Our study reports that 12% of all Afro-Caribbean patients aged > 60 years at SGH were diagnosed with ATTR V122I, a figure with important implications. Specialist amyloidosis investigation was reserved for patients with high clinical suspicion of the disease so the prevalence of ATTR V122I may have been even higher as not all heart failure patients at SGH were referred to the UK NAC for further characterization.The prevalence of ATTR amyloidosis in the general cardiology clinic is significantly higher than would be expected from the recent study of UK death certificate data.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/bjh.12286", "ISSN" : "1365-2141", "PMID" : "23480608", "abstract" : "Epidemiological studies of systemic amyloidosis are scarce and the burden of disease in England has not previously been estimated. In 1999, the National Health Service commissioned the National Amyloidosis Centre (NAC) to provide a national clinical service for all patients with amyloidosis. Data for all individuals referred to the NAC is held on a comprehensive central database, and these were compared with English death certificate data for amyloidosis from 2000 to 2008, obtained from the Office of National Statistics. Amyloidosis was stated on death certificates of 2543 individuals, representing 0\u00b758/1000 recorded deaths. During the same period, 1143 amyloidosis patients followed at the NAC died, 903 (79%) of whom had amyloidosis recorded on their death certificates. The estimated minimum incidence of systemic amyloidosis in the English population in 2008, based on new referrals to the NAC, was 0\u00b74/100 000 population. The incidence peaked at age 60-79 years. Systemic AL amyloidosis was the most common type with an estimated minimum incidence of 0\u00b73/100 000 population. Although there are various limitations to this study, the available data suggest the incidence of systemic amyloidosis in England exceeds 0\u00b78/100 000 of the population.", "author" : [ { "dropping-particle" : "", "family" : "Pinney", "given" : "Jennifer H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Colette J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taube", "given" : "Jessi B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lachmann", "given" : "Helen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Venner", "given" : "Christopher P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gibbs", "given" : "Simon D J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dungu", "given" : "Jason", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Banyperasad", "given" : "Sanjay M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wechalekar", "given" : "Ashutosh D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Carol J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillmore", "given" : "Julian D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "British journal of haematology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "3", "11" ] ] }, "page" : "525-532", "title" : "Systemic Amyloidosis in England: an epidemiological study.", "type" : "article-journal", "volume" : "161" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁶", "plainTextFormattedCitation" : "26", "previouslyFormattedCitation" : "[26]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }26 Retrospective review of death certificates reveals an annual incidence of systemic amyloidosis (all types) of 0.8 per 100,000 UK population, with predominantly Caucasian ethnicity (4.5% black African, black Caribbean or mixed black and other ethnicity nationwide). The low absolute numbers in the wider population likely represents combined underdiagnosis and possible low penetrance of the gene, given the expected allele frequency. The recently reported longitudinal Atherosclerosis Risk in Communities study failed to demonstrate a significant difference in mortality between 124 V122I TTR variant carriers (3%) and 3732 noncarriers, but the incidence of heart failure was higher in allele carriers and median age of carriers at final follow-up is younger than the median age of presentation for ATTR V122I and low proportions of males were included or followed to visit 5.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMoa1404852", "ISSN" : "1533-4406", "PMID" : "25551524", "abstract" : "Background Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. Methods We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. Results After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. Conclusions We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.).", "author" : [ { "dropping-particle" : "", "family" : "Quarta", "given" : "C Cristina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buxbaum", "given" : "Joel N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shah", "given" : "Amil M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falk", "given" : "Rodney H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Claggett", "given" : "Brian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kitzman", "given" : "Dalane W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mosley", "given" : "Thomas H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Butler", "given" : "Kenneth R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boerwinkle", "given" : "Eric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Solomon", "given" : "Scott D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015", "1" ] ] }, "page" : "21-29", "title" : "The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans.", "type" : "article-journal", "volume" : "372" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁷", "plainTextFormattedCitation" : "27", "previouslyFormattedCitation" : "[27]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }27 Wild-type ATTR amyloidosis is reported to be an increasingly important cause of heart failure with preserved ejection fraction (HFpEF) and has been shown to be the primary etiology in up to 13% of patients of all ethnicities. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/eurheartj/ehv338", "ISBN" : "1522-9645 (Electronic)\\r0195-668X (Linking)", "ISSN" : "15229645", "PMID" : "26224076", "abstract" : "AIMS: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes. Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit from new specific treatments. ATTRwt can be diagnosed non-invasively by (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF.\\n\\nMETHODS AND RESULTS: We prospectively screened all consecutive patients \u226560 years old admitted due to HFpEF [left ventricular (LV) ejection fraction \u226550%] with LV hypertrophy (\u226512 mm). All eligible patients were offered a (99m)Tc-DPD scintigraphy. The study included 120 HFpEF patients (59% women, 82 \u00b1 8 years). A total of 16 patients (13.3%; 95% confidence interval: 7.2-19.5) showed a moderate-to-severe uptake on the (99m)Tc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutations were found. An endomyocardial biopsy was performed in four patients, confirming ATTRwt in all cases. There were no differences in age, gender, hypertension, diabetes, coronary artery disease, or atrial fibrillation between ATTRwt patients and patients with other HFpEF forms. Although patients with ATTRwt exhibited higher median N-terminal pro-brain natriuretic peptide (6467 vs. 3173 pg/L; P = 0.019), median troponin I (0.135 vs. 0.025 \u00b5g/L; P < 0.001), mean LV maximal wall thickness (17 \u00b1 3.4 vs. 14 \u00b1 2.5 mm; P = 0.001), rate of pericardial effusion (44 vs. 19%; P = 0.047), and rate of pacemakers (44 vs. 12%; P = 0.004), clinical overlap between ATTRwt and other HFpEF forms was high.\\n\\nCONCLUSION: ATTRwt is an underdiagnosed disease that accounts for a significant number (13%) of HFpEF cases. The effect of emerging TTR-modifying drugs should be evaluated in these patients.", "author" : [ { "dropping-particle" : "", "family" : "Gonz\u00e1lez-L\u00f3pez", "given" : "Esther", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gallego-Delgado", "given" : "Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guzzo-Merello", "given" : "Gonzalo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haro-Del Moral", "given" : "F. Javier", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cobo-Marcos", "given" : "Marta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robles", "given" : "Carolina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bornstein", "given" : "Beln", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salas", "given" : "Clara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lara-Pezzi", "given" : "Enrique", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alonso-Pulpon", "given" : "Luis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garcia-Pavia", "given" : "Pablo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "European Heart Journal", "id" : "ITEM-1", "issue" : "38", "issued" : { "date-parts" : [ [ "2015", "7", "28" ] ] }, "page" : "2585-2594", "title" : "Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁸", "plainTextFormattedCitation" : "28", "previouslyFormattedCitation" : "[28]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }28The geographic origins of the ATTR V122I patients reported here is consistent with a founder mutation in West Africa.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1161/CIRCULATIONAHA.111.078915", "ISSN" : "1524-4539", "PMID" : "22949539", "author" : [ { "dropping-particle" : "", "family" : "Ruberg", "given" : "Frederick L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berk", "given" : "John L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Circulation", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2012", "9", "4" ] ] }, "page" : "1286-300", "title" : "Transthyretin (TTR) Cardiac Amyloidosis.", "type" : "article-journal", "volume" : "126" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁹", "plainTextFormattedCitation" : "29", "previouslyFormattedCitation" : "[29]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }29 During the Atlantic slave trade, from the 16th through to 19th centuries, subjects were transported from West Africa to the Americas and Caribbean. Migration of Caribbeans to the UK, predominantly to London, began following World War II. The latest 2011 UK Census reports that Black African and Caribbean subjects comprised 4.5% of the British population (13.3% of London population), and in the age cohort >70 years, 80% originate from the Caribbean. The lack of a positive family history in the majority of patients suggests that the V122I variant cannot reliably indicate a low penetrance for this disease. Under diagnosis is a likely contributing factor. Worldwide distribution of family members is another factor, and the late onset may contribute to the absence of a family history due to a shorter life expectancy in previous generations and in parts of West Africa.Under-recognition of ATTR V122I amyloidosis is suggested by the observed referral patterns in this study, noting that 25% of the known UK cohort were referred in just 7 years from a single south London center with routine on-site CMR coupled with growing awareness of this disease. A substantial and progressive increase in referrals generally during the past 5 years can be attributed to increased access to CMR elsewhere in the UK.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "doi:10.1136/heartjnl-2012-301924", "abstract" : "Cardiac amyloidosis of transthyretin fibril protein (ATTR) type is an infiltrative cardiomyopathy characterised by ventricular wall thickening and diastolic heart failure. Increased access to cardiovascular magnetic resonance imaging has led to a marked increase in referrals to our centre of Caucasian patients with wild-type ATTR (senile systemic) amyloidosis and Afro-Caribbean patients with the hereditary ATTR V122I type. Both subtypes present predominantly as isolated cardiomyopathy. The differential diagnosis includes cardiac amyloid light-chain (AL) amyloidosis, which has a poorer prognosis and can be amenable to chemotherapy. We review here the clinical features of cardiac ATTR amyloidosis and describe the diagnostic tests to determine ATTR type. Correct diagnosis is ever more crucial given that several novel therapies for ATTR amyloidosis are on the near horizon.", "author" : [ { "dropping-particle" : "", "family" : "Dungu", "given" : "Jason N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anderson", "given" : "Lisa J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Carol J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Heart", "id" : "ITEM-1", "issue" : "21", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "1546-1554", "title" : "Cardiac transthyretin amyloidosis", "type" : "article-journal", "volume" : "98" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶", "plainTextFormattedCitation" : "6", "previouslyFormattedCitation" : "[6]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6 Factors that are likely impeding diagnosis are lack of awareness of this condition, and limited investigation of Afro-Caribbeans with heart failure reported previously.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.amjcard.2005.07.028", "ISSN" : "0002-9149", "PMID" : "16226931", "abstract" : "The demographics of the United States are changing, and in the next few decades there will no longer be a racial/ethnic majority population. Increased awareness of cardiovascular disease (CVD) in special populations is warranted as these populations increase. Heart failure carries a substantial burden on those affected, particularly African Americans, who have a disproportionate burden of heart disease. Current treatments for heart failure include angiotensin-converting enzyme inhibitors, beta-blockers, angiotensin II-receptor antagonists, and vasodilating agents. This review discusses the unique characteristics of CVD in African Americans and addresses the need for targeted treatments to reduce the excess burden found in this population.", "author" : [ { "dropping-particle" : "", "family" : "Yancy", "given" : "Clyde W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of cardiology", "id" : "ITEM-1", "issue" : "7B", "issued" : { "date-parts" : [ [ "2005", "10" ] ] }, "page" : "3i-12i", "title" : "Heart failure in African Americans.", "type" : "article-journal", "volume" : "96" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³", "plainTextFormattedCitation" : "3", "previouslyFormattedCitation" : "[3]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }3 The combination of LVH on ECG and a history of hypertension in half of patients had frequently led to initial misdiagnosis of hypertensive cardiomyopathy. We propose a simple diagnostic algorithm to aid detection of cardiac amyloid in Afro-Caribbean patients who may otherwise be inaccurately labeled as having hypertensive heart disease or non-ischemic DCM (Figure 2). We do not propose use of the algorithm to detect ATTR V122I in Caucasian patients since the relative prevalence is very small. The NHLBI GO Exome Variant Project has not detected the mutation in 8,600 European Americans, indicating that the mutation is effectively nonexistent in Caucasians, contrary to our data. The landmark study by Jacobson et al ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJM199702133360703", "ISSN" : "0028-4793", "PMID" : "9017939", "abstract" : "BACKGROUND: After the age of 60, isolated cardiac amyloidosis is four times more common among blacks than whites in the United States; 3.9 percent of blacks are heterozygous for an amyloidogenic allele of the normal serum carrier protein transthyretin in which isoleucine is substituted for valine at position 122 (Ile 122). We hypothesized that the high prevalence of transthyretin Ile 122 is at least partially responsible for the increased frequency of senile cardiac amyloidosis among blacks. METHODS: Paraffin blocks of cardiac tissue were obtained from an earlier study of 52,370 autopsies in Los Angeles and were examined by immunohistochemical and DNA analyses. Samples were available from 32 of 55 blacks and 20 of 78 whites over 60 years of age with isolated cardiac amyloidosis and from two control groups (228 cases). RESULTS: Transthyretin amyloidosis was identified in 31 of the 32 cardiac-tissue samples from the black patients and in 19 of the 20 samples from the white patients. Six of the 26 analyzable DNA samples (23 percent) from the black patients and none of the 19 samples from the white patients were heterozygous for the Ile 122 variant. Four of 125 DNA samples obtained at autopsy (3.2 percent) from a second, more recent, age-matched cohort of blacks without amyloidosis at the same institution were heterozygous for the transthyretin Ile 122 allele. On reexamination the cardiac tissue from these four patients contained small amounts of amyloid not detected at the initial autopsies. All subjects with the Ile 122 variant had ventricular amyloid. CONCLUSIONS: The assessment of elderly black patients with unexplained heart disease should include a consideration of transthyretin amyloidosis, particularly that related to the Ile 122 allele.", "author" : [ { "dropping-particle" : "", "family" : "Jacobson", "given" : "Daniel R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pastore", "given" : "Raymond D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yaghoubian", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kane", "given" : "Immaculata", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gallo", "given" : "Gloria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buck", "given" : "Francis S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buxbaum", "given" : "Joel N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "New England Journal of Medicine", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "1997", "2" ] ] }, "page" : "466-473", "publisher" : "Mass Med Soc", "title" : "Variant-Sequence Transthyretin (Isoleucine 122) in Late-Onset Cardiac Amyloidosis in Black Americans", "type" : "article-journal", "volume" : "336" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁰", "plainTextFormattedCitation" : "30", "previouslyFormattedCitation" : "[30]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }30 failed to demonstrate the gene mutation in any Caucasian patients and only a few individual cases of Caucasian patients with ATTR V122I have been reported. Novel Treatment Options and Implications for Genetic ScreeningSeveral new pharmacological treatments for ATTR amyloidosis are now in development, comprising RNA inhibitors that suppress TTR production in the liver, and drugs bound by circulating TTR protein that promote its normal soluble non-amyloid conformation. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMe1308768", "ISSN" : "1533-4406", "PMID" : "23984734", "author" : [ { "dropping-particle" : "", "family" : "Lachmann", "given" : "Helen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "8", "29" ] ] }, "page" : "866-8", "title" : "A new era in the treatment of amyloidosis?", "type" : "article-journal", "volume" : "369" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³¹", "plainTextFormattedCitation" : "31", "previouslyFormattedCitation" : "[31]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }31 The siRNA agent ALN-TTRSC (Alnylam Pharmaceuticals) has been shown to suppress TTR production profoundly in ATTR patients and healthy volunteers ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMoa1208760", "ISBN" : "1533-4406 (Electronic)\\r0028-4793 (Linking)", "ISSN" : "1533-4406", "PMID" : "23984729", "abstract" : "BACKGROUND: Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.\\n\\nMETHODS: We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers.\\n\\nRESULTS: Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively.\\n\\nCONCLUSIONS: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; numbers, NCT01148953 and NCT01559077.).", "author" : [ { "dropping-particle" : "", "family" : "Coelho", "given" : "Teresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Adams", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Silva", "given" : "Ana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lozeron", "given" : "Pierre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mant", "given" : "Timothy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perez", "given" : "Javier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chiesa", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Warrington", "given" : "Steve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tranter", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Munisamy", "given" : "Malathy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falzone", "given" : "Rick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harrop", "given" : "Jamie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cehelsky", "given" : "Jeffrey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bettencourt", "given" : "Brian R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geissler", "given" : "Mary", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Butler", "given" : "James S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sehgal", "given" : "Alfica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meyers", "given" : "Rachel E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Qingmin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Borland", "given" : "Todd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hutabarat", "given" : "Renta M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clausen", "given" : "Valerie a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alvarez", "given" : "Rene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "Kevin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gamba-Vitalo", "given" : "Christina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Nochur", "given" : "Saraswathy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vaishnaw", "given" : "Akshay K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sah", "given" : "Dinah W Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gollob", "given" : "Jared a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suhr", "given" : "Ole B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2013", "8", "29" ] ] }, "page" : "819-29", "title" : "Safety and efficacy of RNAi therapy for transthyretin amyloidosis.", "type" : "article-journal", "volume" : "369" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³²", "plainTextFormattedCitation" : "32", "previouslyFormattedCitation" : "[32]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }32 and a phase 3 clinical trial in familial amyloid cardiomyopathy is in progress. A Phase 3 clinical trials of Tafamadis (Vyndaqel?), a TTR stabiliser,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00415-013-7051-7", "ISBN" : "0340-5354", "ISSN" : "03405354", "PMID" : "23974642", "abstract" : "Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.", "author" : [ { "dropping-particle" : "", "family" : "Coelho", "given" : "Teresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maia", "given" : "Luis F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Silva", "given" : "Ana Martins", "non-dropping-particle" : "Da", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cruz", "given" : "Marcia W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plante-Bordeneuve", "given" : "Violaine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suhr", "given" : "Ole B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Conceicao", "given" : "Isabel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Hartmut H J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trigo", "given" : "Pedro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kelly", "given" : "Jeffery W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Labaudiniere", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chan", "given" : "Jason", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Packman", "given" : "Jeff", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grogan", "given" : "Donna R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neurology", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2013", "8", "22" ] ] }, "page" : "2802-2814", "title" : "Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy", "type" : "article-journal", "volume" : "260" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³³", "plainTextFormattedCitation" : "33", "previouslyFormattedCitation" : "[33]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }33 in cardiac ATTR amyloidosis is also in progress. A potential cure for amyloidosis using the immunotherapeutic approach of combining the compound CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid) to clear circulating serum amyloid P component, present in all types of amyloid, and anti-SAP-antibodies has been shown to be safe in a phase 1 trial in man.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMoa1504942", "ISSN" : "1533-4406", "PMID" : "26176329", "abstract" : "Background The amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells. Methods We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored. Results There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed. Conclusions Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; number, NCT01777243 .).", "author" : [ { "dropping-particle" : "", "family" : "Richards", "given" : "Duncan B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cookson", "given" : "Louise M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berges", "given" : "Alienor C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Barton", "given" : "Sharon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lane", "given" : "Thirusha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ritter", "given" : "James M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fontana", "given" : "Marianna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moon", "given" : "James C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pinzani", "given" : "Massimo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gillmore", "given" : "Julian D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hawkins", "given" : "Philip N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pepys", "given" : "Mark B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The New England journal of medicine", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2015", "7", "15" ] ] }, "page" : "1106-14", "title" : "Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.", "type" : "article-journal", "volume" : "373" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁴", "plainTextFormattedCitation" : "34", "previouslyFormattedCitation" : "[34]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }34 The role of this strategy in cardiac involvement is not yet known.The V122I allele is inherited in an autosomal dominant fashion. To date, genetic screening for carriers had been discouraged at this center due to the lack of available treatments. However, screening for early disease in family members and non-invasive surveillance programs will need to be considered as effective treatments emerge for all ATTR subtypes.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/WCO.0000000000000290", "ISBN" : "0000000000000", "ISSN" : "1473-6551", "PMID" : "26734953", "abstract" : "PURPOSE OF REVIEW: These recommendations highlight recent experience in genetic counselling for the severe autosomal-dominant, late-onset transthyretin familial amyloid polyneuropathy (TTR-FAP) disease, and present a structured approach towards identification and monitoring of asymptomatic carriers of the mutated gene.\\n\\nRECENT FINDINGS: The effectiveness of current treatment options is still limited in patients with TTR-FAP beyond stage I. Diagnosis in the early stages of TTR-FAP is essential to prevent or delay the progression of disease. Existing legal and cultural issues differ among countries within Europe. Experts of the European Network for TTR-FAP (ATTReuNET) concluded that genetic counselling for diagnosed individuals and at-risk family members is mostly beneficial and should be carried out with care by trained professionals. Systematic and regular monitoring of an asymptomatic carrier is necessary to detect early signs of TTR-FAP and maximize the effectiveness of treatment. This includes five areas of assessment: history/clinical examination, sensorimotor function, autonomic dysfunction, cardiac function, and renal function. At least two related symptoms and positive biopsy findings are required to confirm diagnosis of TTR-FAP.\\n\\nSUMMARY: Early detection of TTR-FAP is essential to improve the prognosis of TTR-FAP. ATTReuNET recommends genetic counselling and routine monitoring for asymptomatic carriers of TTR-FAP.", "author" : [ { "dropping-particle" : "", "family" : "Obici", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuks", "given" : "Jan B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buades", "given" : "Juan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Adams", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suhr", "given" : "Ole B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Coelho", "given" : "Teresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kyriakides", "given" : "Theodore", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current opinion in neurology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "1", "5" ] ] }, "page" : "S27-35", "title" : "Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis.", "type" : "article-journal", "volume" : "29 Suppl 1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁵", "plainTextFormattedCitation" : "35", "previouslyFormattedCitation" : "[35]" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }35LIMITATIONSWe acknowledge potential selection bias exists for patients presenting to the heart failure clinic. Although we have a robust system for detecting and monitoring patients with an index admission with heart failure, some patients may not have been included in this study and others may not be referred by colleagues in the general medical teams treating heart failure. Despite this, we believe we have identified a relatively large and representative cohort of patients in our catchment area. Etiology of heart failure was determined by the heart failure clinician at the time of diagnosis and reviewed at the time of data collection; this introduces bias but, in our opinion, more accurately classifies patients by diagnosis. Afro-Caribbean patients were less frequently investigated with coronary angiography, based on clinical assessment, thus the low rates of ischemic cardiomyopathy may have been influenced by the index of suspicion. A significant selection bias relating to genetic testing of overt amyloidosis patients only is appreciated but any additional positive results would result in a higher proportion of V122I cases. Survival is reported from the date of diagnosis; whilst we have assessed the duration of symptoms prior to diagnosis, the lag from disease onset to symptoms may be influenced by recall bias. CONCLUSIONConsideration of race in the approach to a patient with heart failure is important for the most personalized management. In London, the etiology of heart failure varies depending on ethnicity and affects age of presentation and outcomes. Non-ischemic DCM, often with preceding history of hypertension and concomitant LVH, is the commonest cause of heart failure in Afro-Caribbeans. For the first time we report the high prevalence of ATTR V122I in the Afro-Caribbean UK heart failure population. The genetically variant allele is carried by up to 4% of African Americans. Penetrance is as yet unknown. We describe the clinical phenotype of patients with ATTR V122I amyloidosis. ATTR V122I amyloidosis does not respond to standard heart failure medications and progresses to death in 2.6 years with intractable heart failure. Phase 3 trials of three separate TTR specific disease modifying agents are in progress, underscoring the importance of awareness and early diagnosis of this otherwise overlooked and rapidly fatal condition. For patients of African descent who present with heart failure and left ventricular wall thickening, regardless of any history of hypertension, ATTR V122I should be considered and actively investigated.AcknowledgementsWe would like to thank the UK National Amyloidosis Centre for confirming the cardiac amyloidosis diagnosis in patients through genetic testing and histological confirmation.Funding sourcesJ.N.D. was supported by a British Heart Foundation Clinical Research Training Fellowship grant no. FS/09/063/28026Disclosures: NoneREFERENCESADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Cleland JGF, McDonagh T, Rigby AS, Yassin A, Whittaker T, Dargie HJ. The national heart failure audit for England and Wales 2008-2009. Heart. 2011;97:876–886. 2. Office for National Statistics (ONS). Ethnicity and National Identity in England and Wales 2011. 2012;3. Yancy CW. Heart failure in African Americans. Am J Cardiol. 2005;96:3i–12i. 4. Gill PS, Calvert M, Davis R, Davies MK, Freemantle N, Lip GYH. Prevalence of heart failure and atrial fibrillation in minority ethnic subjects: the Ethnic-Echocardiographic Heart of England Screening Study (E-ECHOES). PLoS One. 2011;6:e26710. 5. Chaturvedi N, McKeigue PM, Marmot MG. Resting and ambulatory blood pressure differences in Afro-Caribbeans and Europeans. Hypertension. 1993;22:90–6. 6. Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN. Cardiac transthyretin amyloidosis. Heart. 2012;98:1546–1554. 7. Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid. 2015;1–4. 8. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, Falk RH, Cheung KN, Patel AR, Pano A, Packman J, Grogan DR. Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloidosis Cardiac Study (TRACS). Am Heart J. 2012;164:222–228.e1. 9. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29:63–76. 10. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9–13. 11. Casale PN, Devereux RB, Alonso DR, Campo E, Kligfield P. Improved sex-specific criteria of left ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: validation with autopsy findings. Circulation. 1987;75:565–72. 12. Hancock EW, Deal BJ, Mirvis DM, Okin P, Kligfield P, Gettes LS, Bailey JJ, Childers R, Gorgels A, Josephson M, Kors J a, Macfarlane P, Mason JW, Pahlm O, Rautaharju PM, Surawicz B, van Herpen G, Wagner GS, Wellens H. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part V: electrocardiogram changes associated with cardiac chamber hypertrophy: a scientific statement from the American Heart Association Electrocardiography. J Am Coll Cardiol. 2009;53:992–1002. 13. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MSJ, Stewart WJ. 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 Echocardiograph. J Am Soc Echocardiogr. 2005;18:1440–63. 14. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57:450–8. 15. Dungu JN, Valencia O, Pinney JH, Gibbs SDJ, Rowczenio D, Gilbertson JA, Lachmann HJ, Wechalekar A, Gillmore JD, Whelan CJ, Hawkins PN, Anderson LJ. CMR-Based Differentiation of AL and ATTR Cardiac Amyloidosis. JACC Cardiovasc Imaging. 2014;7:133–142. 16. Hundley WG, Bluemke D, Bogaert JG, Friedrich MG, Higgins CB, Lawson MA, McConnell M V, Raman S V, van Rossum AC, Flamm S, Kramer CM, Nagel E, Neubauer S. Society for Cardiovascular Magnetic Resonance guidelines for reporting cardiovascular magnetic resonance examinations. J Cardiovasc Magn Reson. 2009;11:5. 17. Perugini E, Guidalotti PL, Salvi F, Cooke RMT, Pettinato C, Riva L, Leone O, Farsad M, Ciliberti P, Bacchi-Reggiani L, Fallani F, Branzi A, Rapezzi C. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol. 2005;46:1076–84. 18. Talmud P, Tybjaerg-Hansen A, Bhatnagar D, Mbewu A, Miller JP, Durrington P, Humphries S. Rapid screening for specific mutations in patients with a clinical diagnosis of familial hypercholesterolaemia. Atherosclerosis. 1991;89:137–41. 19. Booth DR, Tan SY, Hawkins PN, Pepys MB, Frustaci A. A novel variant of transthyretin, 59Thr-->Lys, associated with autosomal dominant cardiac amyloidosis in an Italian family. Circulation. 1995;91:962–7. 20. Puchtler H, Sweat F, Levine M. On the binding of Congo red by amyloid. J Histochem Cytochem. 1962;10:355. 21. Tennent GA. Isolation and characterization of amyloid fibrils from tissue. Methods Enzymol. 1999;309:26–47. 22. Connors L, Prokaeva T, Lim A, Théberge R, Falk RH, Doros G, Berg A, Costello CE, O’Hara C, Seldin DC, Skinner M. Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158:607–614. 23. Agyemang C, Humphry RW, Bhopal R. Divergence with age in blood pressure in African-Caribbean and white populations in England: implications for screening for hypertension. Am J Hypertens. 2012;25:89–96. 24. Agyemang C, Bhopal R. Is the blood pressure of people from African origin adults in the UK higher or lower than that in European origin white people? A review of cross-sectional data. J Hum Hypertens. 2003;17:523–34. 25. Dungu J, Sattianayagam PT, Whelan CJ, Gibbs SDJ, Pinney JH, Banypersad SM, Rowczenio D, Gilbertson JA, Lachmann HJ, Wechalekar A, Gillmore JD, Hawkins PN, Anderson LJ. The electrocardiographic features associated with cardiac amyloidosis of variant transthyretin Isoleucine 122 (V122I) type in Afro-Caribbean patients. Am Heart J. 2012;164:72–9. 26. Pinney JH, Smith CJ, Taube JB, Lachmann HJ, Venner CP, Gibbs SDJ, Dungu J, Banyperasad SM, Wechalekar AD, Whelan CJ, Hawkins PN, Gillmore JD. Systemic Amyloidosis in England: an epidemiological study. Br J Haematol. 2013;161:525–532. 27. Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, Mosley TH, Butler KR, Boerwinkle E, Solomon SD. The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans. N Engl J Med. 2015;372:21–29. 28. González-López E, Gallego-Delgado M, Guzzo-Merello G, De Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36:2585–2594. 29. Ruberg FL, Berk JL. Transthyretin (TTR) Cardiac Amyloidosis. Circulation. 2012;126:1286–300. 30. Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum JN. Variant-Sequence Transthyretin (Isoleucine 122) in Late-Onset Cardiac Amyloidosis in Black Americans. N Engl J Med. 1997;336:466–473. 31. Lachmann HJ. A new era in the treatment of amyloidosis? N Engl J Med. 2013;369:866–8. 32. Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, Perez J, Chiesa J, Warrington S, Tranter E, Munisamy M, Falzone R, Harrop J, Cehelsky J, Bettencourt BR, Geissler M, Butler JS, Sehgal A, Meyers RE, Chen Q, Borland T, Hutabarat RM, Clausen V a, Alvarez R, Fitzgerald K, Gamba-Vitalo C, Nochur S V, Vaishnaw AK, Sah DWY, Gollob J a, Suhr OB. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369:819–29. 33. Coelho T, Maia LF, Da Silva AM, Cruz MW, Plante-Bordeneuve V, Suhr OB, Conceicao I, Schmidt HHJ, Trigo P, Kelly JW, Labaudiniere R, Chan J, Packman J, Grogan DR. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol. 2013;260:2802–2814. 34. Richards DB, Cookson LM, Berges AC, Barton S V, Lane T, Ritter JM, Fontana M, Moon JC, Pinzani M, Gillmore JD, Hawkins PN, Pepys MB. Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 2015;373:1106–14. 35. Obici L, Kuks JB, Buades J, Adams D, Suhr OB, Coelho T, Kyriakides T. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol. 2016;29 Suppl 1:S27–35. Figure legendsFigure 1 - Kaplan-Meier survival curves demonstrating the difference in survival according to the top 5 causes of heart failure in Afro-Caribbean patients attending the general heart failure clinic and 64 Afro-Caribbean patients with ATTR V122I (UK NAC).Median survival (years): DCM 7.4; HTCM 7.3; VHD 4.8; Ischemic 3.2; ATTR V122I (SGH) 2.3; ATTR V122I (NAC) 2.9Figure 2 - A proposed diagnostic algorithm to detect cases of ATTR amyloidosis in Afro-Caribbean patientsTABLESTable 1Comparison of heart failure patients at St George’s hospital according to ethnicityCaucasian patients (N = 984)Afro-Caribbean patients (N = 211)P value*Age (range)Aged >80 years74 (64-82)325 (33%)71 (54-77)40 (19%)<0.001<0.001Male genderHypertensionCVANYHA class**IIIIIIIV656 (68%)532 (54%)131 (13%)340 (35%)402 (42%)213 (22%)13 (1%)143 (68%)150 (71%)30 (14%)84 (43%)70 (36%)40 (20%)3 (1%)0.76<0.0010.690.24Ischemic cardiomyopathy405 (41%)28 (13%)<0.001Non-ischemic 579 (59%)183 (87%)Cardiac amyloidosis (all types)16 (1.6%)24 (11.4%)<0.001ATTR V122I3 (0.3%)18 (8.5%)<0.001Dilated cardiomyopathy196 (19.9%)58(27.5%)<0.001Hypertensive cardiomyopathy22 (2.2%)26 (12.3%)<0.001Invasive coronary angiography Patients <80 yearsPatients >80 years477 (48%)365 (56%)112 (34%)120 (57%)106 (62%)14(34%)0.160.0820.54EchocardiographyCMR performed984 (100%)210 (21%)211 (100%)87 (41%)NS<0.001CRT device therapyEndomyocardial biopsy257 (26%)31 (3.2%)36 (17%)29 (13.7%)0.006<0.001Sinus rhythmAtrial fibrillationPaced rhythm596 (60.6%)352 (35.8%)36 (3.7%)159 (75.4%)45 (21.3%)7 (3.3%)<0.001LV septal wall thickness, mm (echo)LVEF, % (echo)LVEF <35%, N10 (9-12)40 (30-54)315 (32%)11 (10-14)40 (30-55)80 (38%)<0.0010.930.60Creatinine μmol/LTroponin μg/LNT-pro BNP (ng/L)101 (80-130)0.03 (0-0.09)2459 (848-6525)107 (88-138)0.04 (0-0.12)2195 (654-5132)0.0080.300.17*Compared to Caucasian patients**Caucasian N=968; Afro-Caribbean N = 197CVA – cerebrovascular accident; LVEF – left ventricular ejection fraction; CRT – cardiac resynchronization therapyTable 2Clinical characteristics of patients with biopsy-proven ATTR V122I amyloidosis (NAC)ATTR V122I (N = 72)Age (years)74 ± 6.9 Male gender Black African/Caribbean ethnicity61 (84.7%)64 (89%)NYHA Class IIIIIIIV3 (4.2%)35 (48.6%)31 (43.1%)3 (4.2%)Duration of symptoms before diagnosis (years)1.06 (0.68-2.41)Fluid overload at presentation43 (59.7%)Hypertension34 (47.2%)Type 2 diabetes13 (18.1%)History of CVA6 (8.3%)MGUS17 (23.6%)Creatinine (?mol/L)131 (113-164)eGFR ml/min48 (39-61)*N = 42; NYHA – New York heart Association; CVA – cerebrovascular accident; MGUS – monoclonal gammopathy of uncertain significance detected on serum light chains; ACE – angiotensin converting enzyme; ARB – Angiotensin receptor blocker; eGFR – estimated glomerular filtration rate (correct for ethnicity); NT-pro BNP – N terminal brain natriuretic peptideTable 3 ECG and echocardiographic characteristics of patients with biopsy-proven ATTR V122I amyloidosisECGATTR V122I (N=72)Rate (beats per minute)74 (66-85)RhythmSinusAtrial fibrillation/flutterPaced42 (58%)22 (31%)8 (11%)Axis*NormalLeft axis deviationRight axis deviation17 (26.6%)40 (62.5%)7 (10.9%)PR interval (ms)?198 (174-226)First degree heart block?21 (50%)Low voltage criteria*24 (38%)Left ventricular hypertrophy criteria*11 (17%)Interventricular septum thickness (mm)17 ± 2Posterior wall thickness (mm)17 ± 2End diastolic diameter (mm)43 ± 6End systolic diameter (mm)34 ± 7Left ventricular mass (g)299 (260-354)Left atrial diameter (mm)46 ± 6Left ventricular ejection fraction (%)39 ± 11Diastolic functionNormalGrade 1-2 dysfunctionGrade 3-4 dysfunction0 (0%)41 (57%)31 (43 %)E/A ratio?2.5 ± 0.9E/E’ ratio16 (14-19)Pericardial effusion35 (49%)*Only for 64 non-paced ECGs?Only for 42 patients in sinus ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download