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Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, e0143456Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Transthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex.

MATERIAL AND METHODS: Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness.

RESULTS: There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness.

CONCLUSION: This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

Place, publisher, year, edition, pages
2015. Vol. 10, no 11, e0143456
Keyword [en]
gender, fibril, ATTR, transthyretin, cardiac amyloidosis, age
National Category
Cardiac and Cardiovascular Systems
URN: urn:nbn:se:umu:diva-113831DOI: 10.1371/journal.pone.0143456ISI: 000365853900127OAI: diva2:890732
Available from: 2016-01-04 Created: 2016-01-04 Last updated: 2016-05-19Bibliographically approved
In thesis
1. Cardiac function in hereditary transthyretin amyloidosis: an echocardiographic study
Open this publication in new window or tab >>Cardiac function in hereditary transthyretin amyloidosis: an echocardiographic study
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Hjärtfunktion vid ärftlig transtyretin-amyloidos : en ekokardiografisk studie
Abstract [en]

Background: Hereditary transthyretin amyloidosis (ATTR) is a lethal disease in which misfolded transthyretin (TTR) proteins accumulate as insoluble aggregates in tissues throughout the body. A common mutation is the exchange of valine to methionine at place 30 (TTR V30M), a form endemically found in the northern parts of Sweden. The main treatment option for ATTR amyloidosis is liver transplantation as the procedure halts production of mutated transthyretin. The disease is associated with marked phenotypic diversity ranging from predominant cardiac complications to pure neuropathy. Two different types of fibril composition – one in which both fragmented and full-length TTR are present (type A) and one consisting of only full-length TTR (type B) have been suggested to account for some phenotypic differences. Cardiac amyloidosis is associated with increased myocardial thickness and the disease could easily be mistaken for other entities characterised by myocardial thickening, such as sarcomeric hypertrophic cardiomyopathy (HCM). The aims in this thesis were to investigate echocardiographic characteristics in Swedish ATTR amyloidosis patients, and to identify markers aiding in differentiating ATTR heart disease from HCM. Another objective was to examine the impact of fibril composition and sex on the phenotypic variation in amyloid heart disease.

Methods: A total of 122 ATTR amyloidosis patients that had undergone thorough echocardiographic examinations were included in the studies. Analyses of ventricular geometry as well as assessment of systolic and diastolic function were performed, using both conventional echocardiographic methods and speckle tracking technique. ECG analysis was conducted in study I, allowing measurement of QRS voltage. In study I and study II ATTR patients were compared to patients with HCM. In addition, 30 healthy controls were added to study II.

Results: When parameters from ECG and echocardiography were investigated, the results revealed that the combination of QRS voltage <30 mm (<3 mV) and an interventricular/posterior wall thickness quotient <1.6 could differentiate cardiac ATTR amyloidosis from HCM. Differences in degree of right ventricular involvement were also demonstrated between HCM and ATTR amyloidosis, where ATTR patients displayed a right ventricular apical sparing pattern whereas the inverse pattern was found in HCM. Analysis of fibril composition revealed increased LV wall thickness in type A patients compared to type B, but in addition type A women displayed both lower myocardial thickness and more preserved systolic function as compared to type A males. When cardiac geometry and function were evaluated pre and post liver transplantation in type A and B patients, significant deterioration was detected in type A but not in type B patients after liver transplantation.

Conclusions: Increasing awareness of typical cardiac amyloidotic signs by echocardiography is important to reduce the risk of delayed diagnosis. Our classification model based on ECG and echocardiography could aid in differentiating ATTR amyloidosis from HCM. Furthermore, the apical sparing pattern found in the right ventricle may pose another clue for amyloid heart disease, although it requires to be studied further. Furthermore, we disclosed that type A fibrils, male sex and increasing age were important determinants of increased myocardial thickness. As type A fibril patients displayed rapid cardiac deterioration after liver transplantation other treatment options should probably be sought for this group of patients.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. 56 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1774
Amyloid, echocardiography, ECG, HCM, fibril type, strain, ATTR, cardiomyopathy, speckle tracking
National Category
Cardiac and Cardiovascular Systems Other Clinical Medicine
urn:nbn:se:umu:diva-113891 (URN)978-91-7601-399-1 (ISBN)
Public defence
2016-01-29, Hörsal Betula Unod L0, Umeå, 09:00 (Swedish)
Available from: 2016-01-08 Created: 2016-01-04 Last updated: 2016-01-07Bibliographically approved

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