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Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy?
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, Cardiology. (Heart Centre)
Umeå University, Faculty of Medicine, Department of Radiation Sciences.ORCID iD: 0000-0003-0081-1156
Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
Umeå University, Faculty of Medicine, Department of Radiation Sciences.ORCID iD: 0000-0002-1313-0934
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2015 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, no 3, p. 163-170Article 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.

Place, publisher, year, edition, pages
2015. Vol. 22, no 3, p. 163-170
Keywords [en]
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
Identifiers
URN: urn:nbn:se:umu:diva-109962DOI: 10.3109/13506129.2015.1037831ISI: 000361295200004PubMedID: 26104852Scopus ID: 2-s2.0-84940032324OAI: oai:DiVA.org:umu-109962DiVA, id: diva2:859982
Available from: 2015-10-09 Created: 2015-10-09 Last updated: 2023-03-24Bibliographically 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. p. 56
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1774
Keywords
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: 2018-06-07Bibliographically approved
2. Patient stratification and treatment effects in diseases with disturbed cardiac function
Open this publication in new window or tab >>Patient stratification and treatment effects in diseases with disturbed cardiac function
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Cardiovascular disease characteristics are often measured using a combination of different measurement modalities. By combining information from these modalities using statistical modelling we can gain additional knowledge about these diseases. 

Patients with hereditary transthyretin amyloidosis (ATTRv amyloidosis) often present with heart rate disturbances and ventricular hypertrophy. Although ATTRv amyloidosis can lead to a thick ventricular myocardium and heart failure this can also be due to other pathologies e.g. hypertrophic cardiomyopathy (HCM), which may lead to misdiagnosis. Children with hereditary long QT syndrome (LQTS) carry the risk of lethal cardiac events linked to increased sympathetic activity. If the regulatory pattern, measured by heart rate variability (HRV), could differentiate between LQTS genotypes and healthy children during childhood, it may then establish a role for HRV in evaluating such patients. Statins is the most common pharmaceutical treatment for atherosclerosis. However, the effect of statins on coronary calcification has shown mixed results between studies.

Aim: The overall aim of this thesis was to use statistically rigorous methodology to explore stratification of subgroups of patients and estimate treatment effects in diseases with cardiac involvement. The specific aims were: to evaluate discriminating features between ATTRv amyloidosis and HCM patients in different clinical examinations of their hearts; to evaluate the longitudinal growth pattern in HRV in children with LQTS; and, to estimate the short- and long-term treatment effects of statin treatment on coronary calcification in patients with coronary arteriosclerosis. 

Methods: In Study I we used classification and regression trees in order to create a clinical interpretable decision tree in order to differentiate between 35 ATTRv amyloidosis patients and 37 HCM patients based on features derived from echocardiography and ECG. In Study II a retrospective sample of 38 ATTRv amyloidosis patients, 41 HCM patients and 62 healthy controls were analyzed using k-means clustering and Random forest models in order to investigate similarities and differences in echocardiographic features and HRV. In Study III we calculated gender and treatment dependent age trends for spectral HRV features from longitudinal measurements from 70 children with LQTS (58 LQT1, 12 LQT2) and 65 healthy controls, using generalized additive mixed effects models. In Study IV data from two large clinical trials, in total 1585 patients with mild cardiac symptoms, was used to estimate the short- and long-term treatment effects of statin treatment on coronary calcification.

Results: In study I we found that a decision tree using both ECG and echocardiographic measurements provided the best separation between HCM and ATTRv amyloidosis. In study II we found that HRV could be used for discriminating between these diseases and that abnormalities in HRV are related on ATTRv fibril type but uncommon in HCM. In study III we found that the age trend in HRV in LQTS-patients showed no clear differences between controls and patients different LQTS genotypes. In study IV we found that high dose statin treatment resulted in a dose dependent increase in calcium score at both short- and long-term follow up. At the long-term follow up, we found no evidence to suggest that the increased calcium score had resulted in increased cardiac events.

Conclusions: The results from our studies could be used for differentiating HCM and ATTRv amyloidosis patients. The heterogeneity within these patient groups could further be characterized using features from echocardiography and HRV. Our data do not support evidence for a different age trend in HRV parameters in children with LQTS compared to controls of similar age. We also found that statin treatment increased calcium score on both short-and long-term follow up. Taken together the results and methods from this thesis may be used for future support in clinical decisions regarding patient stratification and knowledge of treatment effects.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2020. p. 82
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2089
Keywords
Biostatistics, Heart rate variability, Cardiac amyloidosis, hypertrophic cardiomyopathy, cluster analysis, Echocardiography, Long QT syndrome, Pediatric, Statins, Coronary artery calcium, Computer tomography, Machine learning, Predictive modeling
National Category
Medical Engineering
Identifiers
urn:nbn:se:umu:diva-173971 (URN)978-91-7855-311-2 (ISBN)978-91-7855-310-5 (ISBN)
Public defence
2020-09-04, Sal 933, Unod B9, 9tr. Norrlands Universitetssjukhus, Norrlands Universitetssjukhus, Daniel Naezéns väg, 907 37 Umeå, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2020-08-17 Created: 2020-08-11 Last updated: 2020-08-12Bibliographically approved

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Gustavsson, SandraGranåsen, GabrielGrönlund, ChristerWiklund, UrbanMörner, StellanHenein, MichaelSuhr, Ole BLindqvist, Per

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Amyloid: Journal of Protein Folding Disorders
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)Cardiac and Cardiovascular Systems

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