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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
Identifiers
URN: urn:nbn:se:umu:diva-113831DOI: 10.1371/journal.pone.0143456ISI: 000365853900127OAI: oai:DiVA.org:umu-113831DiVA: diva2:890732
Available from: 2016-01-04 Created: 2016-01-04 Last updated: 2017-12-01Bibliographically 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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1774
Keyword
Amyloid, echocardiography, ECG, HCM, fibril type, strain, ATTR, cardiomyopathy, speckle tracking
National Category
Cardiac and Cardiovascular Systems Other Clinical Medicine
Identifiers
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)
Opponent
Supervisors
Available from: 2016-01-08 Created: 2016-01-04 Last updated: 2016-01-07Bibliographically approved
2. The heart in hereditary transthyretin amyloidosis: clinical studies on the impact of amyloid fibril composition
Open this publication in new window or tab >>The heart in hereditary transthyretin amyloidosis: clinical studies on the impact of amyloid fibril composition
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Hereditary transthyretin amyloid (ATTRm) amyloidosis is a systemic disease mainly affecting the peripheral nervous system and the heart. The disease is inherited in an autosomal dominant manner with a varying penetrance. It is caused by mutations in the transthyretin (TTR) gene. Today more than 100 disease causing mutations are known. The V30M mutation that is endemic in northern Sweden is the best studied and comprises the majority of the reported disease cases in the world. In ATTRm amyloidosis caused by the V30M mutation two distinct sub populations are seen, one with disease onset early in life and a mainly neuropathic disease and the other with late onset disease and both neuropathic disease and a progressive cardiomyopathy. These phenotypical findings have in Swedish patients been tied to differences in amyloid fibril composition. Generally, patients with early onset disease have amyloid fibrils containing only full length transthyretin (type B) whereas patients with late onset disease have amyloid containing both full length and fragmented transthyretin (type A). Until recently, the only available treatment for the disease has been liver transplantation. Patients with type A fibrils, especially males, have significantly worse survival after liver transplant due to progressive amyloid cardiomyopathy. Furthermore, it appears that type A fibrils may be the most common finding in other mutations.

This thesis work aims to in depth investigate the impact amyloid fibril composition has on cardiac manifestations of the disease and on the outcome of available and novel modalities for cardiac amyloid imaging.

Methods The four studies included in the thesis were done as part of the on going clinical research at the Swedish centre for transthyretin amyloidosis in Umeå.  Patients in whom amyloid fibril composition had been determined were included. Available echocardiographic data were analysed to find predictors for left ventricular hypertrophy and systolic function as measured by strain analysis in a large cohort of 105 patients (paper I). Serial 12-lead electrocardiograms from 98 patients were gathered and retrospectively interpreted and analysed to investigate the impact of amyloid fibril composition and disease progression on frequency and development of ECG abnormalities (paper IV).  DPD scintigraphy, cardiac biomarkers, clinical data and echocardiograms were analysed in a cohort of 53 consecutive patients. to assess the impact of amyloid fibril composition on the outcome of DPD scintigraphy and its relationship with cardiac hypertrophy. (paper II). To evaluate the usefulness of positron emission tomography (PET) using the amyloid specific tracer PIB, 10 patients, five with each fibril type, were selected and examined. The patients selected had a similar age of onset and similar echocardiographic findings (paper III).

Results Paper I: Type A fibrils, male gender and age were independent factors associated with increased LV thickness. The distribution of amyloid fibril composition did not differ between the sexes, but in patients with type A fibrils, females had lower median cardiac wall thickness (p<0.01and better left ventricular septal strain (p=0.04).The gender differences were not apparent in patients with type B fibrils.

Paper II: Ninety-seven per cent of patients with type A fibrils had pathological cardiac DPD uptake compared to none of the patients with type B fibrils. Among patients with normal septal thickness, none of 15 patients with type B fibrils had positive scintigraphy compared with 2 out of 2 with type A fibrils (P<0.01) Cardiac biomarkers, demographic data and cardiac biomarkers were significantly different, but could not differentiate between type A and type B fibrils in individual patients.

Paper III: All patients had pathological cardiac PIB retention. In patients with type B fibrils the retention was significantly higher (p<0.01) than in patients with type A fibrils. Based on the selection criteria, no significant differences were seen in various echocardiographic measurements.

Paper IV: All patients had a high prevalence of AV-blocks, LAH and anterior infarction pattern. Patients with type A fibrils had significantly more electrocardiographic abnormalities compared to those with type B fibrils, both at an early stage of diseases and at later follow up.

Conclusion Type A fibrils are associated with more pronounced cardiac involvement, which appear to be more severe in males than in females. In study II we showed that DPD scintigraphy appears to be a very good tool for non-invasive determination of amyloid fibril composition. Papers III and IV show that patients with type B amyloid have cardiac involvement even without echocardiographic or DPD-scintigraphic evidence of amyloid cardiomyopathy and that ECG abnormalities are common irrespectively of amyloid fibril composition, and increase with time for both groups. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2017. 55 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1904
Keyword
Amyloidosis, Transthyretin, Cardiomyopathy, Echocardiography, Scintigraphy, Positron emission tomography
National Category
Cardiac and Cardiovascular Systems
Research subject
Medicine, cardiovascular disease; Cardiology; Clinical Physiology
Identifiers
urn:nbn:se:umu:diva-139495 (URN)978-91-7601-745-6 (ISBN)
Public defence
2017-10-06, Sal D, 9 tr, Norrlands universitetssjukhus, Umeå, 17:00 (Swedish)
Opponent
Supervisors
Funder
Swedish Heart Lung Foundation
Available from: 2017-09-15 Created: 2017-09-14 Last updated: 2017-09-26Bibliographically approved

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