umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The heart in hereditary transthyretin amyloidosis: clinical studies on the impact of amyloid fibril composition
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.ORCID iD: 0000-0002-4963-3971
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 [en]
Amyloidosis, Transthyretin, Cardiomyopathy, Echocardiography, Scintigraphy, Positron emission tomography
National Category
Cardiac and Cardiovascular Systems
Research subject
Medicine, cardiovascular disease; Cardiology; Clinical Physiology
Identifiers
URN: urn:nbn:se:umu:diva-139495ISBN: 978-91-7601-745-6 (print)OAI: oai:DiVA.org:umu-139495DiVA: diva2:1141459
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
List of papers
1. Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition
Open this publication in new window or tab >>Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition
Show others...
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.

Keyword
gender, fibril, ATTR, transthyretin, cardiac amyloidosis, age
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-113831 (URN)10.1371/journal.pone.0143456 (DOI)000365853900127 ()
Available from: 2016-01-04 Created: 2016-01-04 Last updated: 2017-09-14Bibliographically approved
2. 99mTC-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis
Open this publication in new window or tab >>99mTC-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis
Show others...
2016 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 1, 17-24 p.Article in journal (Refereed) Published
Abstract [en]

Aims In transthyretin amyloid (ATTR) amyloidosis various principal phenotypes have been described: cardiac, neuropathic, or a mixed cardiac and neuropathic. In addition, two different types of amyloid fibrils have been identified (type A and type B). Type B fibrils have thus far only been found in predominantly early-onset V30M and in patients carrying the Y114C mutation, whereas type A is noted in all other mutations currently examined as well as in wild-type ATTR amyloidosis. The fibril type is a determinant of the ATTR V30M disease phenotype. Tc-99m-DPD scintigraphy is a highly sensitive method for diagnosing heart involvement in ATTR amyloidosis. The objective of this study was to determine the relationship between ATTR fibril composition and Tc-99m-DPD scintigraphy outcome in patients with biopsy-proven ATTR amyloidosis. Methods Altogether 55 patients with biopsy-proven diagnosis of ATTR amyloidosis and amyloid fibril composition determined were examined by Tc-99m-DPD scintigraphy. The patients were grouped and compared according to their type of amyloid fibrils. Cardiovascular evaluation included ECG, echocardiography, and cardiac biomarkers. The medical records were scrutinized to identify subjects with hypertension or other diseases that have an impact on cardiac dimensions. Results A total of 97% with type A and none of the patients with type B fibrils displayed Tc-99m-DPD uptake at scintigraphy (p < 0.001). Findings from analyses of cardiac biomarkers, ECG, and echocardiography, though significantly different, could not differentiate between type A and B fibrils in individual patients. Conclusion In ATTR amyloidosis, the outcome of Tc-99m-DPD scintigraphy is strongly related to the patients' transthyretin amyloid fibril composition.

Place, publisher, year, edition, pages
Taylor & Francis, 2016
Keyword
transthyretin, Amyloidosis hereditary, echocardiography, scintigraphy, amyloid cardiomyopathy
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-119085 (URN)10.3109/03009734.2015.1122687 (DOI)000372123700003 ()26849806 (PubMedID)
Available from: 2016-04-19 Created: 2016-04-11 Last updated: 2017-09-14Bibliographically approved
3. Positron emission tomography (PET) utilizing Pittsburgh compound B (PIB) for detection of amyloid heart deposits in hereditary transthyretin amyloidosis (ATTR)
Open this publication in new window or tab >>Positron emission tomography (PET) utilizing Pittsburgh compound B (PIB) for detection of amyloid heart deposits in hereditary transthyretin amyloidosis (ATTR)
Show others...
2016 (English)In: Journal of Nuclear Cardiology, ISSN 1071-3581, E-ISSN 1532-6551Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background: DPD scintigraphy has been advocated for imaging cardiac amyloid in ATTR amyloidosis. PET utilizing 11C-Pittsburgh compound B (PIB) is the gold standard for imaging brain amyloid in Alzheimer’s disease. PIB was recently shown to identify cardiac amyloidosis in both AL and ATTR amyloidosis. In the ATTR population, two types of amyloid fibrils exist, one containing fragmented and full-length TTR (type A) and the other only full-length TTR (type B). The aim of this study was to further evaluate PIB-PET in patients with hereditary ATTR amyloidosis.

Methods: Ten patients with biopsy-proven V30M ATTR amyloidosis and discrete or no signs of cardiac involvement were included. Patients were grouped according to TTR-fragmentation. All underwent DPD scintigraphy, echocardiography, and PIB-PET. A left ventricular PIB-retention index (PIB-RI) was established and compared to five normal volunteers.

Results: PIB-RI was increased in all patients (P < 0.001), but was significantly higher in type B than in type A (0.129 ± 0.041 vs 0.040 ± 0.006 min−1, P = 0.009). Cardiac DPD uptake was elevated in group A and absent in group B.

Conclusion: PIB-PET, in contrast to DPD scintigraphy, has the potential to specifically identify cardiac amyloid depositions irrespective of amyloid fibril composition. The heart appears to be a target organ for amyloid deposition in ATTR amyloidosis.

Keyword
Cardiomyopathy, amyloidosis, Pittsburgh compound B
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-127300 (URN)10.1007/s12350-016-0638-5 (DOI)2-s2.0-84988421982 (Scopus ID)
Available from: 2016-11-07 Created: 2016-11-07 Last updated: 2017-09-15
4. Electrocardiographic features of hereditary V30M transthyretin amyloidosis, different phenotypes with similar findings
Open this publication in new window or tab >>Electrocardiographic features of hereditary V30M transthyretin amyloidosis, different phenotypes with similar findings
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-139531 (URN)
Available from: 2017-09-15 Created: 2017-09-15 Last updated: 2017-09-15

Open Access in DiVA

fulltext(11112 kB)39 downloads
File information
File name FULLTEXT01.pdfFile size 11112 kBChecksum SHA-512
5d2956df334f4a3432f266e3bd98ab3b54f19e11129e15f25f4325ce8538abbe6641305caa918aef6de30e329b8114efce7425abaf6544473636e4fe985705ae
Type fulltextMimetype application/pdf
spikblad(133 kB)6 downloads
File information
File name SPIKBLAD01.pdfFile size 133 kBChecksum SHA-512
a00bad2290d2bc420a6924a0132d84d1dea53a8311af2a240f76155f1c3011007cb2218eb84965a76e79d33342810e23b2d7d7526ffce4f133f8cdfa7b53fc8e
Type spikbladMimetype application/pdf

Search in DiVA

By author/editor
Pilebro, Björn
By organisation
Medicine
Cardiac and Cardiovascular Systems

Search outside of DiVA

GoogleGoogle Scholar
Total: 39 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 618 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf