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Cardiac function in hereditary transthyretin amyloidosis: an echocardiographic study
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Hjärtfunktion vid ärftlig transtyretin-amyloidos : en ekokardiografisk studie (Swedish)
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
Keyword [en]
Amyloid, echocardiography, ECG, HCM, fibril type, strain, ATTR, cardiomyopathy, speckle tracking
National Category
Cardiac and Cardiovascular Systems Other Clinical Medicine
URN: urn:nbn:se:umu:diva-113891ISBN: 978-91-7601-399-1OAI: diva2:890771
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
List of papers
1. Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy?
Open this publication in new window or tab >>Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy?
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2015 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, no 3, 163-170 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Hereditary transthyretin (ATTR) amyloidosis with increased left ventricular wall thickness could easily be misdiagnosed by echocardiography as hypertrophic cardiomyopathy (HCM). Our aim was to create a diagnostic tool based on echocardiography and ECG that could optimise identification of ATTR amyloidosis. Methods: Data were analysed from 33 patients with biopsy proven ATTR amyloidosis and 30 patients with diagnosed HCM. Conventional features from ECG were acquired as well as two dimensional and Doppler echocardiography, speckle tracking derived strain and tissue characterisation analysis. Classification trees were used to select the most important variables for differentiation between ATTR amyloidosis and HCM. Results: The best classification was obtained using both ECG and echocardiographic features, where a QRS voltage >30 mm was diagnostic for HCM, whereas in patients with QRS voltage <30 mm, an interventricular septal/posterior wall thickness ratio (IVSt/PWt) >1.6 was consistent with HCM and a ratio <1.6 supported the diagnosis of ATTR amyloidosis. This classification presented both high sensitivity (0.939) and specificity (0.833). Conclusion: Our study proposes an easily interpretable classification method for the differentiation between HCM and increased left ventricular myocardial thickness due to ATTR amyloidosis. Our combined echocardiographic and ECG model could increase the ability to identify ATTR cardiac amyloidosis in clinical practice.

cardiac amyloidosis, classification tree, echocardiography, electrocardiography, hypertrophic rdiomyopathy, hypertrophy
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cardiac and Cardiovascular Systems
urn:nbn:se:umu:diva-109962 (URN)10.3109/13506129.2015.1037831 (DOI)000361295200004 ()26104852 (PubMedID)
Available from: 2015-10-09 Created: 2015-10-09 Last updated: 2016-01-07Bibliographically approved
2. Right ventricular involvement in transthyretin amyloidosis
Open this publication in new window or tab >>Right ventricular involvement in transthyretin amyloidosis
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(English)Manuscript (preprint) (Other academic)
Abstract [en]


Right heart involvement and dysfunction is frequently encountered in cardiomyopathies. In immunoglobulin light chain (AL) amyloidosis, right ventricular (RV) function has been described as a strong determinant of survival. However, RV involvement in transthyretin related amyloidosis (ATTR) has been somewhat overlooked. We therefore sought to establish the degree of RV involvement in ATTR amyloidosis and compare the findings with sarcomeric hypertrophic cardiomyopathy (HCM).

Patients and methods

Forty-two patients with diagnosed ATTR and echocardiographic evidence of cardiac amyloidosis (cardiac ATTR), 19 ATTR patients with normal left ventricular (LV) wall thickness (non-cardiac ATTR), 25 patients with diagnosed sarcomeric HCM and 30 healthy controls were included in the study. Echocardiographic examinations were analysed and standard measurements of LV and RV dimensions and function were carried out. In addition, LV global and RV global and segmental strain were analysed. The degree of cardiac involvement and function was compared between non-cardiac ATTR patients and healthy controls and between cardiac ATTR patients and with those having HCM.


Non-cardiac ATTR amyloidosis patients did not differ from healthy controls, either in geometrical or functional measurements of the LV and RV. HCM patients had significantly thicker interventricular septal thickness (p=0.017) and thinner posterior wall thickness (p=0.004) as compared to cardiac ATTR. When comparing cardiac ATTR and HCM patients by means of RV structure and function only segmental strain differed between the two patient groups. In cardiac ATTR we found an RV apex-to-base strain gradient with highest deformation in the apex whereas the pattern was inverse in patients with HCM.


RV involvement is common only in ATTR patients with concomitant LV involvement. The present study also detected an apical sparing pattern for the RV in patients with ATTR cardiomyopathy, similar to what has previously been described for the LV. This pattern was not seen in HCM patients. Further studies are warranted to assess the clinical importance of these findings.

Cardiac amyloidosis, hypertrophic cardiomyopathy, HCM, strain, apical sparing
National Category
Cardiac and Cardiovascular Systems
urn:nbn:se:umu:diva-113889 (URN)
Available from: 2016-01-04 Created: 2016-01-04 Last updated: 2016-01-08
3. 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
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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.

gender, fibril, ATTR, transthyretin, cardiac amyloidosis, age
National Category
Cardiac and Cardiovascular Systems
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: 2016-05-19Bibliographically approved
4. Amyloid Fibril Composition as a Predictor of Development of Cardiomyopathy After Liver Transplantation for Hereditary Transthyretin Amyloidosis
Open this publication in new window or tab >>Amyloid Fibril Composition as a Predictor of Development of Cardiomyopathy After Liver Transplantation for Hereditary Transthyretin Amyloidosis
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2012 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 93, no 10, 1017-1023 p.Article in journal (Refereed) Published
Abstract [en]

Background. Liver transplantation (LTx) is an accepted treatment for hereditary transthyretin (TTR) amyloidosis (ATTR). However, unforeseen heart complications, especially a rapid development of cardiomyopathy after LTx has affected mortality and morbidity. Recently, a relationship between ATTR-fibril composition and cardiomyopathy has been noted. The aim of this study was to investigate whether development of cardiomyopathy and heart failure in LTx ATTR amyloid patients is related to amyloid fibril composition. Methods. Twenty-four patients with hereditary ATTR amyloidosis who had undergone LTx and have had their amyloid fibril type tested were available for the study. They had been examined by echocardiography including tissue Doppler and speckle tracking echocardiography before and after LTx. Patients were divided into two groups according to fibril composition, 10 patients with type A fibrils (a mixture of truncated and full-length TTR) and 14 patients with type B fibrils (full-length TTR fibrils only). There was no difference in time to the follow-up echocardiography between the two groups. Results. After LTx, the group consisting of type A patients developed symptoms of heart failure and with reduced systolic and diastolic ventricular function as shown by echocardiography, whereas no similar deterioration was noted for the group of patients with type B fibrils. Conclusion. Patients with type A fibrils deteriorate an already existing cardiomyopathy and heart failure after LTx, in contrast to patients with type B fibrils. These results might have significant clinical implications in optimizing best patients selection criteria for LTx.

National Category
Clinical Medicine
urn:nbn:se:umu:diva-56994 (URN)10.1097/TP.0b013e31824b3749 (DOI)000304866100012 ()
Available from: 2012-07-04 Created: 2012-07-02 Last updated: 2016-01-07Bibliographically approved

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