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Arvidsson, Sandra
Alternative names
Publications (10 of 16) Show all publications
Arvidsson, S., Eriksson, R., Anan, I. & Heldestad, V. (2023). Enlarged cross-sectional area in peripheral nerves in Swedish patients with hereditary V30M transthyretin amyloidosis. Annals of Medicine, 55(2), Article ID 2239269.
Open this publication in new window or tab >>Enlarged cross-sectional area in peripheral nerves in Swedish patients with hereditary V30M transthyretin amyloidosis
2023 (English)In: Annals of Medicine, ISSN 0785-3890, E-ISSN 1365-2060, Vol. 55, no 2, article id 2239269Article in journal (Refereed) Published
Abstract [en]

Introduction: In hereditary transthyretin amyloidosis (ATTRv), two different fibrillar forms causing the amyloid deposition, have been identified, displaying substantially cardiac or neuropathic symptoms. Neuropathic symptoms are more frequent in early-onset patients, whereas late-onset patients, besides cardiac symptoms, seem to develop carpal tunnel syndrome, more often. With ultrasonography (US) of peripheral nerves, it is possible to distinguish structural changes, and enlarged cross-sectional area (CSA). The main purpose of this study was, for the first time, to elucidate US of peripheral nerves in Swedish ATTRv patients at an early stage of the disease, and to evaluate possible early enlarged CSA.

Material and methods: This prospective study included first visit data of 13 patients, aged 30–88 years, of which 11 with late-onset age. All had a positive V30M mutation. Eight men and six women (aged 28–74 years) served as controls.

Results: Significantly enlarged CSA was seen in ATTRv patients for the tibial nerve at the ankle (p =.001), the sural nerve (p <.001), the peroneal nerve at the popliteal fossa (p =.003), and the ulnar nerve at the middle upper arm (p =.007).

Conclusion: US of peripheral nerves could be a valuable tool in disease evaluation and could facilitate monitoring of disease progression.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2023
Keywords
Hereditary transthyretin amyloidosis, nerve cross-sectional area, nerve entrapments, peripheral nerves, ultrasonography
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-214062 (URN)10.1080/07853890.2023.2239269 (DOI)37619249 (PubMedID)2-s2.0-85168627277 (Scopus ID)
Funder
Umeå University, 2022-06-10Knut and Alice Wallenberg Foundation, RV-762081
Available from: 2023-09-05 Created: 2023-09-05 Last updated: 2024-03-19Bibliographically approved
Erelund, S., Karp, K., Arvidsson, S., Johansson, B., Sundström, N. & Wiklund, U. (2023). Pulmonary function in a cohort of heart-healthy individuals from Northern Sweden: a comparison with discordant reference values. BMC Pulmonary Medicine, 23(1), Article ID 110.
Open this publication in new window or tab >>Pulmonary function in a cohort of heart-healthy individuals from Northern Sweden: a comparison with discordant reference values
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2023 (English)In: BMC Pulmonary Medicine, E-ISSN 1471-2466, Vol. 23, no 1, article id 110Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Dynamic spirometry is an important investigation to differentiate between impaired and normal lung function. This study aimed to evaluate the results of lung function testing in a cohort of subjects from Northern Sweden without any known heart or pulmonary disease. Our focus was to compare with two reference materials that have showed differences in the age-dependency of lung function in Swedish subjects.

METHODS: The study population consisted of 285 healthy adults (148 males, 52%) between 20-90 years of age. The subjects had been randomly selected from the population register for inclusion in a study investigating cardiac function in heart-healthy subjects, but were also assessed with dynamic spirometry. At least seven percent reported smoking. Sixteen subjects presented with pulmonary functional impairments and were excluded from the current study. The sex-specific age-dependency in lung volumes was estimated using the LMS model, where non-linear equations were derived for the mean value (M), the location (L) or skewness, and the scatter (S) or coefficient of variation. This model of the observed lung function data was compared with reference values given by the original LMS model published by the Global Lung Initiative (GLI), and with the model from the recent Obstructive Lung Disease In Norrbotten (OLIN) study, where higher reference values were presented for Swedish subjects than those given by the GLI model.

RESULTS: No differences were found in the age-dependency of pulmonary function between the LMS model developed in the study and the OLIN model. Although the study group included smokers, the original GLI reference values suggested significantly lower normal values of FEV1 (forced expiratory volume) and FVC (forced vital capacity), and consequently fewer subjects below the lower limit of normality, than both the rederived LMS and OLIN models.

CONCLUSIONS: Our results are in line with previous reports and support that the original GLI reference values underestimate pulmonary function in the adult Swedish population. This underestimation could be reduced by updating the coefficients in the underlying LMS model based on a larger cohort of Swedish citizens than was available in this study.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Clinical physiology, Linear regression, Lung function, Reference values, Spirometry
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-206770 (URN)10.1186/s12890-023-02403-w (DOI)000963360400001 ()37020237 (PubMedID)2-s2.0-85151789612 (Scopus ID)
Available from: 2023-04-26 Created: 2023-04-26 Last updated: 2024-01-17Bibliographically approved
Erelund, S., Karp, K., Wiklund, U., Hörnsten, R. & Arvidsson, S. (2021). Are ECG changes in heart-healthy individuals of various ages related to cardiac disease 20 years later?. Upsala Journal of Medical Sciences, 126(1), Article ID e6064.
Open this publication in new window or tab >>Are ECG changes in heart-healthy individuals of various ages related to cardiac disease 20 years later?
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2021 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 126, no 1, article id e6064Article in journal (Refereed) Published
Abstract [en]

Background: This research study aimed at assessing the electrocardiographic (ECG) changes caused by ageing in a cohort of healthy subjects with normal echocardiographic examinations.

Methods: A total of 219 healthy individuals (119 males and 100 females) were evaluated for possible arrhythmias with a standard 12-lead resting ECG and 24-h Holter ECG. As the recordings were performed between 1998 and 2000, a 20-year follow-up study was carried out by assessing the local medical records to investigate whether the subjects had experienced any cardiovascular health complications or disease since the baseline assessment.

Results: Eighty-three subjects (45 males and 38 females) presented with pathological ECG findings at baseline. The most common finding on analysis of Holter ECG recordings was premature atrial contractions, and the most severe pathological finding was episodes of ventricular tachycardia (eight subjects). Regarding the analysis of the standard 12-lead ECG, the most common finding was left ventricular hypertrophy, and the most severe pathological findings were ST-T changes and prolongation of the QT interval. Despite other cardiac examinations performed on these patients showing normal results, in combination with a strict inclusion criterion, this study showed that 28% of all subjects had pathological resting 12-lead ECGs at rest and 35% had pathological heart rhythms when assessed by 24-h Holter ECG. At follow-up, 21% of females and 43% of males had presented with ECG abnormalities, and 30% of females and 36% of males had cardiovascular disease. There was hypertension in 45% of females and in 58% of males. However, no association was found between the follow-up findings and ECG changes seen at baseline.

Conclusion: Although most ECG changes found at baseline could be considered as a normal variation, they may progress to more severe heart complications as the subject ages. The results of this study also validate ECG findings of previous studies and underline that diagnostic criteria should be based on gender and age.

Place, publisher, year, edition, pages
Upsala Medical Society, 2021
Keywords
Arrhythmia, Clinical physiology, Electrocardiogram, Heart function test, Normal values
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-186419 (URN)10.48101/ujms.v126.6064 (DOI)000683141300001 ()2-s2.0-85110436769 (Scopus ID)
Funder
Region Västerbotten
Available from: 2021-07-29 Created: 2021-07-29 Last updated: 2023-11-02Bibliographically approved
Pilebro, B., Arvidsson, S., Lindqvist, P., Sundström, T., Westermark, P., Antoni, G., . . . Sörensen, J. (2018). Positron emission tomography (PET) utilizing Pittsburgh compound B (PIB) for detection of amyloid heart deposits in hereditary transthyretin amyloidosis (ATTR). Journal of Nuclear Cardiology, 25(1), 240-248
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)
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2018 (English)In: Journal of Nuclear Cardiology, ISSN 1071-3581, E-ISSN 1532-6551, Vol. 25, no 1, p. 240-248Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
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)000423585200038 ()27645889 (PubMedID)2-s2.0-84988421982 (Scopus ID)
Available from: 2016-11-07 Created: 2016-11-07 Last updated: 2019-05-21Bibliographically approved
Arvidsson, S., Henein, M. Y., Wikström, G., Suhr, O. B. & Lindqvist, P. (2018). Right ventricular involvement in transthyretin amyloidosis. Amyloid: Journal of Protein Folding Disorders, 25(3), 160-166
Open this publication in new window or tab >>Right ventricular involvement in transthyretin amyloidosis
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2018 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, no 3, p. 160-166Article in journal (Refereed) Published
Abstract [en]

Background: The extent of right ventricular (RV) involvement in transthyretin amyloidosis (ATTR) is unknown.

Objectives: This study sought to establish the degree of RV involvement in ATTR amyloidosis, and compare findings with RV involvement in hypertrophic cardiomyopathy (HCM).

Methods: Forty-two patients with ATTR amyloidosis 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 HCM and 30 healthy controls were included in this study. Echocardiographic measurements for conventional parameters, as well as RV global and segmental strain, were recorded.

Results: When comparing RV structure and function between cardiac ATTR amyloidosis and HCM patients, only segmental strain differed between the two groups. In cardiac ATTR amyloidosis, we found an RV apex-to-base strain gradient with highest deformation in the apex. This pattern was reversed in patients with HCM.

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

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
Hypertrophic cardiomyopathy, apical sparing, strain, amyloid cardiomyopathy, right ventricle
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-113889 (URN)10.1080/13506129.2018.1493989 (DOI)000451980700004 ()30193533 (PubMedID)2-s2.0-85053299450 (Scopus ID)
Note

Originally included in thesis in manuscript form.

Available from: 2016-01-04 Created: 2016-01-04 Last updated: 2023-03-23Bibliographically approved
Arvidsson, S. (2016). Cardiac function in hereditary transthyretin amyloidosis: an echocardiographic study. (Doctoral dissertation). Umeå: Umeå universitet
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
Henein, M., Arvidsson, S., Pilebro, B., Backman, C., Mörner, S. & Lindqvist, P. (2016). Long mitral valve leaflets determine left ventricular outflow tract obstruction during exercise in hypertrophic cardiomyopathy. International Journal of Cardiology, 212, 47-53
Open this publication in new window or tab >>Long mitral valve leaflets determine left ventricular outflow tract obstruction during exercise in hypertrophic cardiomyopathy
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2016 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 212, p. 47-53Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Development of left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic cardiomyopathy (HCM) is important for explaining symptoms and designing management. LVOTO is mostly caused by a combination of septal hypertrophy and systolic anterior movement of the mitral valve (SAM). The aim of the present study was to determine predictors of exercise induced LVOTO in a group of HCM patients.

METHODS: We performed supine exercise Doppler echocardiography, including measurements of LV morphology and function and anterior mitral leaflet length, in 51 mildly symptomatic HCM (septal thickness≥15mm) and compared them with 50 healthy controls. Measurements were made at 1) rest, 2) Valsalva maneuver, 3) peak exercise and 4) post exercise. LVOTO was diagnosed as a LVOT gradient of >30mmHg at rest, after Valsalva and after exercise or ≥50mmHg at peak exercise.

RESULTS: All patients stopped exercise because of exhaustion. 35% of the patients had resting LVOTO and 48% during Valsalva. At peak exercise, only 37% had LVOTO, who increased to 64% post exercise. Patients who developed LVOTO at peak exercise were more prone to continue having it post exercise (p<0.001), to have attenuated systolic blood pressure rise (p=0.011) and to have long anterior mitral valve leaflets (p<0.001). Backward multiple regression analysis showed the anterior mitral leaflet length as the strongest single independent predictor (β=0.36, p=0.010) for increased LVOT velocities, followed by basal septal thickness.

CONCLUSION: In patients with HCM, LV outflow tract obstruction seems to be relatively uncommon during exercise but rather occurring minutes after stopping exercise. Exercise LVOTO seems to be determined by long anterior mitral leaflets in addition to the well established septal hypertrophy.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
transthyretin, Amyloidosis hereditary, echocardiography, scintigraphy, amyloid cardiomyopathy, VEREUX RB, 1986, AMERICAN JOURNAL OF CARDIOLOGY, V57, P450 bue G, 2003, AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS5th Int Symp on Familial yloidotic Polyneuropathy and Other Transthyretin Related Disorders/4th Int Workshop on Liver ansplantation in Familial Amyloid Polyneuropathy, SEP 24-27, 2002, MATSUMOTO, JAPAN, V10, P32 gueh Sherif F., 2009, EUROPEAN JOURNAL OF ECHOCARDIOGRAPHY, V10, P165 ille M, 2002, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, V29, P376
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-119478 (URN)10.1016/j.ijcard.2016.03.041 (DOI)000374474600012 ()27031819 (PubMedID)2-s2.0-84962138775 (Scopus ID)
Available from: 2016-04-20 Created: 2016-04-20 Last updated: 2023-03-24Bibliographically approved
Arvidsson, S., Pilebro, B., Westermark, P., Lindqvist, P. & Suhr, O. B. (2015). Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition. PLOS ONE, 10(11), Article ID e0143456.
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, E-ISSN 1932-6203, Vol. 10, no 11, article id 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.

Keywords
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 ()2-s2.0-84957899493 (Scopus ID)
Available from: 2016-01-04 Created: 2016-01-04 Last updated: 2023-03-24Bibliographically approved
Ramzy, I. S., Gustafsson, S., Holmgren, A. & Henein, M. Y. (2015). Early effect of surgical revascularisation on left ventricular twist function. International Cardiovascular Forum Journal, 4, 16-23
Open this publication in new window or tab >>Early effect of surgical revascularisation on left ventricular twist function
2015 (English)In: International Cardiovascular Forum Journal, ISSN 2410-2636, Vol. 4, p. 16-23Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Barcaray Publishing, 2015
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-55469 (URN)10.17987/icfj.v4i0.125 (DOI)
Available from: 2012-05-16 Created: 2012-05-16 Last updated: 2018-11-28Bibliographically approved
Gustavsson, S., Pilebro, B., Westermark, P., Lindqvist, P. & Suhr, O. B. (2015). Gender related differences in cardiac function in patients with hereditary transthyretin amyloidosis. European Journal of Heart Failure, 17, 64-65
Open this publication in new window or tab >>Gender related differences in cardiac function in patients with hereditary transthyretin amyloidosis
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2015 (English)In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 17, p. 64-65Article in journal, Meeting abstract (Other academic) Published
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-113880 (URN)000366200401188 ()
Note

Supplement: 1, Special Issue: SI, Meeting Abstract: P300

Available from: 2016-01-07 Created: 2016-01-04 Last updated: 2018-06-07Bibliographically approved
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