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  • 1.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Liszewska, Katarzyna
    Department of Medicine, Piteå Hospital, Piteå, Sweden.
    Baranda, Jorge Mejia
    Department of Medicine, Piteå Hospital, Piteå, Sweden.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ihse, Elisabet
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Amyloid fibril composition type is consistent over time in patients with Val30Met (p. Val50Met) transthyretin amyloidosis2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 3, article id e0266092Article in journal (Refereed)
    Abstract [en]

    Background: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses.

    Material and methods: Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot.

    Results: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies.

    Discussion: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.

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  • 2.
    Arnberg, Elsa
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Eldhagen, Per
    Cardiology Unit, Department of Medicine, Karolinska Institute, Sweden.
    Löfbacka, Viktor
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Venkateshvaran, Ashwin
    Cardiology Unit, Department of Medicine, Karolinska Institute, Sweden.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    RWT/SaVR-A Simple and Highly Accurate Measure Screening for Transthyretin Cardiac Amyloidosis2022In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 11, no 14, article id 4120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cardiac amyloidosis is an underdiagnosed condition and simple methods for accurate diagnosis are warranted. We aimed to validate a novel, dual-modality approach to identify transthyretin cardiac amyloidosis (ATTR-CA), employing echocardiographic relative wall thickness (RWT), and ECG S-wave from aVR (SaVR), and compare its accuracy with conventional echocardiographic approaches.

    MATERIAL AND METHODS: We investigated 102 patients with ATTR-CA and 65 patients with left ventricular hypertrophy (LVH), all with septal thickness > 14 mm. We validated the accuracy of echocardiographic measures, including RWT, RWT/SaVR, posterior wall thickness (PWT), LV mass index (LVMI), left atrial volume index (LAVI), global longitudinal strain (GLS), and relative apical sparing (RELAPS) to identify ATTR-CA diagnosed using DPD-scintigraphy or abdominal fat biopsy.

    RESULTS: PWT, RWT, RELAPS, troponin, and RWT/SaVR were significantly higher in ATTR-CA compared to LVH. RWT/SaVR > 0.7 was the most accurate parameter to identify ATTR-CA (sensitivity 97%, specificity 90% and accuracy 91%). RELAPS was found to have much less accuracy (sensitivity 74%, specificity 76% and accuracy 73%).

    CONCLUSION: We can confirm the very strong diagnostic accuracy of RWT/SaVR to identify ATTR-CA in patients with septal thickness > 14 mm. Given its high sensitivity and specificity, RWT/SaVR > 0.7 has the potential to implement as a non-invasive, simple, and widely available diagnostic tool when screening for ATTR-CA.

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  • 3.
    Arvidsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Westermark, Per
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143456Article in journal (Refereed)
    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.

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  • 4.
    Gustavsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Westermark, P.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gender related differences in cardiac function in patients with hereditary transthyretin amyloidosis2015In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 17, p. 64-65Article in journal (Other academic)
  • 5.
    Harms, Hendrik J.
    et al.
    Department of Surgical Sciences, Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden; Clinical Institute, Aarhus University, Aarhus, Denmark.
    Clemmensen, Tor
    Clinical Institute, Aarhus University, Aarhus, Denmark.
    Rosengren, Sara
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Tolbod, Lars
    Clinical Institute, Aarhus University, Aarhus, Denmark.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wikström, Gerhard
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Granstam, Sven-Olof
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Kero, Tanja
    Department of Surgical Sciences, Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Di Carli, Marcelo
    Brigham and Women's Hospital, MA, Boston, United States.
    Poulsen, Steen Hvitfeldt
    Clinical Institute, Aarhus University, Aarhus, Denmark.
    Sorensen, Jens
    Department of Surgical Sciences, Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden; Clinical Institute, Aarhus University, Aarhus, Denmark.
    Association of right ventricular myocardial blood flow with pulmonary pressures and outcome in cardiac amyloidosis2023In: JACC Cardiovascular Imaging, ISSN 1936-878X, E-ISSN 1876-7591Article in journal (Refereed)
    Abstract [en]

    Background: Cardiac amyloidosis (CA) is a restrictive and infiltrative cardiomyopathy, characterized by increased biventricular filling pressures and low output. Symptoms are predominantly of right heart origin. The role of right ventricular (RV) myocardial blood flow (MBF) in CA has not been studied.

    Objectives: This study aimed to first associate RV MBF measured by using positron emission tomography (PET) with reference standards of RV pressures and then to explore its prognostic value in CA.

    Methods: Cardiac PET was performed at rest in 52 patients with CA and 9 healthy control subjects. MBF was quantified from the right and left ventricles by using 11C-acetate, 15O-water, or both (n = 25). RV pressure was measured invasively or by echocardiography. Associations between biventricular MBF toward symptoms, RV function, and outcome (death or acute heart failure) were studied in patients with CA.

    Results: MBF of the right ventricle (MBFRV) and the ratio of MBFRV and MBF of the left ventricle (MBFRV/LV) for the 2 tracers were significantly correlated (r > 0.92). MBFRV was directly correlated with RV systolic pressures with both tracers (P ≤ 0.005). MBFLV was inversely correlated with wall thickness (P < 0.0001). MBFRV/LV was significantly associated with N-terminal pro–B-type natriuretic peptide levels, New York Heart Association functional class, RV pressures, and RV systolic function (all; P < 0.001). Twenty-six cardiac events (25 deaths) occurred during follow-up (median 44 months). MBFRV/LV higher than 56% was associated with a diagnosis of pulmonary hypertension (AUC: 0.96 [95% CI: 0.91-1.00]; P < 0.0001); and predicted outcome with hazard ratio 9.0 (95% CI: 4.2-14.5), P < 0.0001).

    Conclusions: Measurements of MBFRV using PET are feasible, as confirmed with 2 different tracers. Imbalance between RV and LV myocardial perfusion is associated with increased RV load and adverse events in cardiac amyloidosis.

  • 6.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lång, Kenneth
    Department of Medicine, Piteå Hospital , Piteå , Sweden..
    Ihse, Elisabet
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 6, p. 372-376Article in journal (Refereed)
    Abstract [en]

    For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

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  • 7.
    Henein, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Arvidsson, Sandra
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Backman, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Long mitral valve leaflets determine left ventricular outflow tract obstruction during exercise in hypertrophic cardiomyopathy2016In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 212, p. 47-53Article in journal (Refereed)
    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.

  • 8.
    Henein, Michael Y.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Disease progression in cardiac morphology and function in heart failure: ATTR cardiac amyloidosis versus hypertensive left ventricular hypertrophy2022In: Heart and Vessels, ISSN 0910-8327, E-ISSN 1615-2573, Vol. 37, p. 1562-1569Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is today more frequently recognized but the rate of progression of cardiac dysfunction is not well established. The aim of this study is to investigate the nature of cardiac structure and function changes, over time, in a retrospective cohort of ATTR-CA patients.

    METHODS: Fifty-one patients with ATTR-CA (mean age 78 ± 7 years, 30 females) were compared with 20 patients with heart failure but no amyloidosis (HFnCA) (mean age 76 ± 7 years, 5 females), all with septal thickness >  = 14 mm. All patients underwent DPD scintigraphy and an echocardiogram (Echo 2) which was compared with a previous echocardiographic examination (Echo 1), performed at least 3 years before.

    RESULTS: Over the follow-up period, the interventricular septal thickness (IVST) and relative wall thickness (RWT) in ATTR-CA increased from 16 (4) to 18 (5) mm and from 0.51 (0.17) to 0.62 (0.21) respectively, p < 0.001 for both, by a mean increase of 0.4 mm/year and 0.03 mm/year, (p = 0.009 and p = 0.002 compared with HFnCA), respectively. RWT > 0.45 (AUC = 0.77) and RELAPS > 2.0 (AUC 0.86) both predicted positive DPD diagnosis for ATTR-CA.

    CONCLUSION: In ATTR-CA patients, the overtime-increase in RWT and IVST was worse than that seen in patients with heart failure but no cardiac amyloidosis. Also, RWT and relative apical sparing predicted diagnosis of ATTR-CA, thus could strengthen the use of follow-up echocardiographic findings as red flag for the diagnosis of ATTR-CA.

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  • 9.
    Henein, Michael Y.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Arvidsson, Sandra
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Westermark, Per
    Hörnsten, Rolf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Reduced left atrial myocardial deformation irrespective of cavity size: a potential cause for atrial arrhythmia in hereditary transthyretin amyloidosis2018In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, no 1, p. 46-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cardiac amyloidosis (CA) is a myocardial disease and commonly under-diagnosed condition. In CA patients, atrial fibrillation might occur in the absence of left atrial (LA) enlargement.

    OBJECTIVES: The aim of this study is to assess LA size and function, and its relationship with atrial arrhythmia in patients with hereditary transthyretin amyloidosis (ATTR).

    METHODS: Forty-six patients with confirmed ATTR amyloidosis on abdominal biopsy were studied. Assessment with 2D echocardiography and 2D strain showed 31 patients had increased LV wall thickness (LVWT) (septal thickness >12 mm), and 15 had normal LVWT. In addition to conventional measurements, LV and LA global longitudinal strain (GLS%) and strain rate (SR) were obtained. Western blot analysis was done to assess fibril type. ATTR patients with increased LVWT were compared with 23 patients with hypertrophic cardiomyopathy (HCM) and 31 healthy controls. ATTR amyloidosis patients also underwent 24 hour Holter monitoring to determine the presence of atrial arrhythmia.

    RESULTS: Atrial deformation during atrial systole was reduced in ATTR amyloidosis patients with increased LVWT independent of LA size and in contrast to HCM. Twenty of the ATTR amyloidosis patients (54%) had ECG evidence of significant atrial arrhythmic events. LA strain rate, during atrial systole, was the only independent predictor of atrial arrhythmia (β = 3.28, p = .012).

    CONCLUSION: In ATTR cardiomyopathy with increased LVWT, LA myocardial function is abnormal, irrespective of atrial cavity size. Reduced LA myocardial SR during atrial systole, irrespective of cavity volume, E/e' and LV deformation, is also a strong predictor for atrial arrhythmic events.

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  • 10.
    Lindmark, Krister
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Solekrans, L.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Prevalence of transthyretin cardiac amyloidosis in a community-based heart failure population2019In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 40, p. 132-132Article in journal (Other academic)
  • 11.
    Lindmark, Krister
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Prevalence of wild type transtyrethin cardiac amyloidosis in a heart failure clinic2021In: ESC Heart Failure, E-ISSN 2055-5822, Vol. 8, no 1, p. 745-749Article in journal (Refereed)
    Abstract [en]

    Aims: Wild type transthyretin amyloidosis (ATTRwt) has gained interest during recent years due to better diagnostic tools and the emergence of treatment options. Little is known about the prevalence of the disease. We aimed to investigate the prevalence in a heart failure population with myocardial hypertrophy.

    Methods and results: All patients with an ICD code of heart failure living within the catchment area of Umeå University hospital and intraventricular septum >14 mm were offered screening with 3,3‐diphosphono‐1,2‐propanodicarboxylic acid (DPD) scan and a clinical work up. Out of 2238 patients with heart failure, 174 patients were found to have a septum >14 mm. Ten patients were already diagnosed with hereditary ATTR cardiomyopathy, 12 patients had ATTRwt cardiomyopathy, 12 patients had known HCM, one patient had AL amyloidosis, and four patients had already undergone a negative DPD scan (DPD uptake grade 0 and 1) within the last 3 years. This left 134 patients who we tried to contact for screening, but 48 patients had either died or declined to participate. Out of 86 screened patients, 13 had a DPD uptake of grade 2 or 3 without other amyloid disease making the total number of patients with ATTRwt in this population 25.

    Conclusions: Approximately 20% of investigated patients in a cohort with heart failure and increased myocardial wall thickness has ATTRwt. Calculated for the whole population of heart failure patients, the prevalence is just over 1.1%. Comparing this number to the total population would give an estimated prevalence of 1:6000.

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  • 12.
    Löfbacka, Viktor
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Cardiac transthyretin amyloidosis 99mTc-DPD SPECTcorrelates with strain echocardiography and biomarkers2021In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 48, p. 1822-1832Article in journal (Refereed)
    Abstract [en]

    Purpose: Hereditary transthyretin-amyloid amyloidosis (ATTRv) is an underdiagnosed condition commonly manifesting as congestive heart failure. Recently, scintigraphy utilizing DPD as a tracer was shown to identify ATTRv and wild-type ATTR cardiomyopathy. The aim of this study was to determine the value of quantified scintigraphy utilizing 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) single-photon emission computed tomography (SPECT)/CT, and to correlate its uptake with well-established cardiac functional parameters.

    Methods: Forty-eight patients with genetically verified ATTRv type-A fibril composition, positive 99mTc-DPD SPECT/CT, were retrospectively analyzed. Manual mapping of volumes of interest (VOIs) on DPD SPECT/CT examinations was used to quantify heart uptake. DPD mean and maximum uptake together with a calculated DPD-based amyloid burden (DPDload) was correlated with echocardiographic strain values and cardiac biomarkers.

    Results: Statistically significant correlations were seen in VOIs between DPD uptakes and the corresponding echocardiographic strain values. Furthermore, DPDload had a strong correlation with echocardiographic strain parameters and also correlated with biomarkers troponin T and logarithmic NT-ProBNP.

    Conclusions: In patients with ATTRv cardiomyopathy, DPD SPECT/CT measures the amyloid distribution and provides information on cardiac amyloid load. DPD amyloid load correlates with functional cardiac parameters.

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  • 13.
    Löfbacka, Viktor
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Combining ECG and echocardiography to identify transthyretin cardiac amyloidosis in heart failure2021In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 41, no 5, p. 408-416Article in journal (Refereed)
    Abstract [en]

    AIMS/BACKGROUND: Transthyretin amyloid (ATTR) amyloidosis cardiomyopathy is an underdiagnosed, causatively treatable cause of heart failure. The aim of this study was to evaluate the efficacy of electrocardiography (ECG) and echocardiography on patients with increased interventricular septum diameter (IVSd) to identify ATTR cardiac amyloidosis (ATTR-CA) patients.

    METHODS: We investigated 58 patients with heart failure and an IVSd >14mm. Included were 33 ATTR-CA patients and 25 controls that consisted of non-amyloidosis heart failure (HF) patients with negative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy. We used echocardiography including 2D speckle tracking strain and a 12-lead ECG to test the accuracy to differentiate the groups.

    RESULTS: We found high diagnostic accuracy (98%) for differentiating ATTR-CA from HF controls using a combination of R amplitude in -aVR from ECG and relative wall thickness acquired from echocardiography. With this combined model (RWT/ R in -aVR), the sensitivity was 100% and specificity was 95% using a cut off value of 0.90. Furthermore, the area under the curve was 99% and the negative predictive value was 100%.

    CONCLUSION: We found that a simple combination of ECG and echocardiographic parameters used in clinical settings was able to differentiate ATTR-CA from other etiologies of HF with increased interventricular septum thickness. The high sensitivity and negative predictive value render the algorithm useful for selection of patients for further diagnostic procedures for ATTR-CA.

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  • 14.
    Möckelind, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Quantification of cardiac amyloid with [18F]Flutemetamol in patients with V30M hereditary transthyretin amyloidosis2020In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 27, no 3, p. 191-199Article in journal (Refereed)
    Abstract [en]

    Background: Hereditary transthyretin amyloid (ATTRv) is a systemic amyloidosis with mainly neurological and cardiac symptoms. The aim of this study was to evaluate the outcome of [18F]Flutemetamol PET/CT-scan of the heart in long-term survivors with ATTRV30M amyloidosis.

    Methods: Twenty-one patients with ATTRV30M amyloidosis and predominantly neurological symptoms, mainly negative on cardiac 99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD)-scintigraphy, were examined with a dynamic [18F]Flutemetamol PET/CT-scan. Five patients suffering from Alzheimer’s disease and one healthy individual served as controls. Volumes of interests were drawn over the intraventricular septum, lateral wall of the left ventricle and free wall of the right ventricle. Clinical records were reviewed for data from previous completed DPD-scintigraphy of the heart and echocardiography.

    Results: Patients with ATTRv amyloidosis had a higher cardiac uptake than the control-group in all analysed regions of the heart and could be identified with high accuracy (sensitivity 88%, specificity 100%) in static image acquisition at 30 or 60 min. We found no correlation between cardiac [18F]Flutemetamol uptake and clinical variables.

    Conclusion: In this small study of selected patients, cardiac [18F]Flutemetamol PET/CT could differentiate between healthy individuals and patients with ATTRV30M. [18F]Flutemetamol PET/CT imaging of amyloidosis in patients with a negative DPD-scintigraphy has a potential as a diagnostic method.

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  • 15.
    Paulsson Rokke, Hedvig
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sadat Gousheh, Nima
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ihse, Elisabet
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspected transthyretin amyloidosis2020In: Orphanet Journal of Rare Diseases, E-ISSN 1750-1172, Vol. 15, no 1, article id 278Article in journal (Refereed)
    Abstract [en]

    Background: The diagnostic accuracy of histopathological detection of transthyretin amyloid (ATTR) by Congo red staining of abdominal fat samples has been questioned since low sensitivity has been reported, especially for patients with ATTR cardiomyopathy. However, the outcome of surgically obtained fat pad biopsies has not yet been evaluated. The aim was to evaluate the diagnostic accuracy of skin punch biopsies from abdominal fat in patients with suspected ATTR amyloidosis.

    Material and methods: Data were evaluated from patients who had undergone abdominal fat pad biopsies using a skin punch due to suspected amyloidosis from 2006 to 2015. The biopsies had been analysed using Congo red staining to determine the presence of amyloid, and immunohistochemistry or Western blot to determine the type of amyloidosis. The final diagnosis was based on the clinical picture, biopsy results and DNA sequencing. Minimum follow-up after the initial biopsy was 3 years.

    Results: Two hundred seventy-four patients (61% males) were identified, and in 132 (48%), a final diagnosis of amyloidosis had been settled. The majority (93%) had been diagnosed with hereditary transthyretin (ATTRv) amyloidosis, and therefore subsequent analyses were focused on these patients. Overall, our data showed a test specificity of 99% and a sensitivity of 91%. Ninety-eight (94%) of the patients had neuropathic symptoms at diagnosis, whereas 57 (55%) had signs of amyloid cardiomyopathy. Subgroup analyses showed that patients with merely neuropathic symptoms displayed the highest test sensitivity of 91%, whereas patients with pure cardiomyopathy displayed the lowest sensitivity of 83%. However, no significant differences in sensitivity were found between patients with or without cardiomyopathy or between the sexes.

    Conclusions: Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspect ATTRv amyloidosis, including patients presenting with cardiomyopathy. In addition, the method enables typing not only of the precursor protein but also of the amyloid fibril type, which is related to the phenotype and to the outcome of the disease.

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  • 16.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    The heart in hereditary transthyretin amyloidosis: clinical studies on the impact of amyloid fibril composition2017Doctoral 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. 

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  • 17.
    Pilebro, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Arvidsson, Sandra
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Westermark, Per
    Antoni, Gunnar
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sörensen, Jens
    Positron emission tomography (PET) utilizing Pittsburgh compound B (PIB) for detection of amyloid heart deposits in hereditary transthyretin amyloidosis (ATTR)2018In: Journal of Nuclear Cardiology, ISSN 1071-3581, E-ISSN 1532-6551, Vol. 25, no 1, p. 240-248Article in journal (Refereed)
    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.

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  • 18.
    Pilebro, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Suhr, Ole B
    Ihse, Elisabeth
    Näslund, Ulf
    Westermark, Per
    Hörnsten, Rolf
    Electrocardiographic features of hereditary V30M transthyretin amyloidosis, different phenotypes with similar findingsManuscript (preprint) (Other academic)
  • 19.
    Pilebro, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Westermark, Per
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    99mTC-DPD uptake reflects amyloid fibril composition in hereditary transthyretin amyloidosis2016In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 1, p. 17-24Article in journal (Refereed)
    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.

  • 20.
    Schmidt, Hartmut H.
    et al.
    Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, University of Duisburg-Essen (formerly of University Hospital Munster, Munster, Germany), Essen, Germany.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Planté-Bordeneuve, Violaine
    Department of Neurology, East Paris University, Hospital Henri Mondor – Public Assistance Hospital of Paris, Créteil, France; Mondor Biomedical Research Institute – IMRB, INSERM, U955 Team 10 “Biology of the Neuro-Muscular System”, Créteil, France.
    Muñoz-Beamud, Francisco
    Hereditary Amyloidosis Unit, Department of Internal Medicine, Juan Ramón Jiménez Hospital, Huelva, Spain.
    Lladó, Laura
    Liver Transplantation Unit, Department of Surgery, and the Multidisciplinary Familial Amyloidosis Unit, Hospital Universitari de Bellvitge, Barcelona, Spain; Biomedical Research Institute, IDIBELL, University of Barcelona, Barcelona, Spain.
    Gillmore, Julian D.
    National Amyloidosis Centre, Division of Medicine, University College London Medical School, London, United Kingdom.
    Mazzeo, Anna
    Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
    Li, Xingyu
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Arum, Seth
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Jay, Patrick Y.
    Alnylam Pharmaceuticals, Inc, MA, Cambridge, United States.
    Adams, David
    Neurology Department, Université Paris-Saclay, U1195, INSERM, Le Kremlin Bicêtre, France; Neurology Department, AP-HP, CHU Bicêtre, Le Kremlin Bicêtre, France.
    Anan, Intissar (Contributor)
    Umeå University Hospital.
    Nordh, Erik (Contributor)
    Umeå University Hospital.
    Unéus, Erica (Contributor)
    Umeå University Hospital.
    Pilebro, Björn (Contributor)
    Umeå University Hospital.
    Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation2022In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 22, no 6, p. 1646-1657Article in journal (Refereed)
    Abstract [en]

    Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%–92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, −3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, −6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, −5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807).

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  • 21.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    The Swedish landscape of hereditary ATTR amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 1, p. 93-94Article in journal (Refereed)
    Abstract [en]

    Northern Sweden is a well-known clustering area for hereditary transthyretin (TTR) amyloid (ATTR) amyloidosis caused by the Val30Met mutation. However, several additional mutations have been found in the Swedish population, of which many, such as the Ala45Ser, Gly57Arg and His88Arg mutations, have not been reported outside of Sweden to the best of our knowledge. We aim to give an overview of the various mutations found in the Swedish population.

  • 22.
    Unéus, Erica Irene
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wilhelmsson, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Bäckström, David
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ögren, Mattias
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ögren, Margareta
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Cerebellar and Cerebral Amyloid Visualized by [18F]flutemetamol PET in Long-Term Hereditary V30M (p.V50M) Transthyretin Amyloidosis Survivors2022In: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 13, article id 816636Article in journal (Refereed)
    Abstract [en]

    Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS.

    Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8–25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls.

    Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD.

    Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.

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  • 23.
    Unéus, Erica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wilhelmsson, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Åhlström Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sundström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Visualisation of amyloid deposition within the brain of long-term hereditary transthyretin amyloidosis survivors by 18F-flutemetamol positron emission tomography2019In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 26, no S1, p. 287-287, article id EPR3027Article in journal (Other academic)
    Abstract [en]

    Background and aims: Hereditary transthyretin amyloid (ATTRv) amyloidosis caused by the transthyretin (TTR) Val30Met (p.V50M) mutation is characterised by peripheral neuropathy, and central nervous (CNS) complications has rarely been reported. However, liver transplantation has prolonged the patients’ survival, and CNS complications attributed to amyloid angiopathy caused by CNS synthesis of variant TTR have been reported. The aim of the study was to ascertain CNS amyloid deposition in long-term ATTRv survivors.

    Methods: 20 ATTR Val30Met patients with symptoms from the CNS and a median disease duration of 16 years (9-25 years) together with five Alzheimer (AD) patients, who served as positive controls were included in the study. Amyloid CNS deposits were assessed by 18F- flutemetamol PET/CT examination utilising relative z scores with pons as reference.

    Results: Expectedly, all Alzheimer patients had an clearly increased global composite z score above 2.0 compared with 55% of the ATTRv patients. There was an increased local uptake corresponding to cerebellum in 12 ATTRv patients compared to only one in the AD group (fig 1). Four of these ATTRv patients had a global composite z score within the normal range. No correlation between duration after 9 years and amyloid CNS deposition was noted.

    Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is increased and is often noted in the cerebellum. However, not all patient display amyloid CNS deposition, thus, additional causes for CNS complications should always be considered.

  • 24.
    Wange, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ericzon, Bo-Göran
    Pennlert, Johanna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Atrial Fibrillation and Central Nervous Complications in Liver Transplanted Hereditary Transthyretin Amyloidosis Patients2018In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 102, no 2, p. e59-e66Article in journal (Refereed)
    Abstract [en]

    Background. Central nervous system (CNS) complications are increasingly noted in liver transplanted (LTx) hereditary transthyretin amyloid (ATTRm) amyloidosis patients; this suggests that the increased survival allows for intracranial ATTRm formation from brain synthesized mutant TTR. However, atrial fibrillation (AF), a recognised risk factor for ischemic CNS complications, is also observed after LTx. The aim of the study was to investigate the occurrence of CNS complications and AF in LTx ATTRm amyloidosis patients. Methods. The medical records of all LTx ATTRm amyloidosis patients in the county of Vasterbotten, Sweden, were investigated for information on CNS complications, AF, anticoagulation (AC) therapy, hypertension, cardiac ischemic disease, hypertrophy, and neurological status. Results. Sixty-three patients that had survived for 3 years or longer after LTx were included in the analysis. Twenty-five patients had developed 1 or more CNS complications at a median of 21 years after onset of disease. AF was noted in 21 patients (median time to diagnosis 24 years). Cerebrovascular events (CVE) developed in 17 (median time to event 21 years). CVEs occurred significantly more often in patients with AF (P < 0.002). AC therapy significantly reduced CVEs, including bleeding in patients with AF (P = 0.04). Multivariate analysis identified AF as the only remaining regressor with a significant impact on CVE (hazard ratio, 3.8; 95% confidence interval 1.1-9.5; P = 0.029). Conclusions. AF is an important risk factor for CVE in LTx ATTRm amyloidosis patients, and AC therapy should be considered. However, the increased bleeding risk with AC therapy in patients with intracranial amyloidosis should be acknowledged.

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  • 25.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Bjorn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Effect of doxycycline and ursodeoxycholic acid on transthyretin amyloidosis2017In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 24, no 1, p. 78-79Article in journal (Refereed)
    Abstract [en]

    Doxycycline has been shown to disrupt transthyretin amyloid (ATTR) fibrils [1] and tauro-ursodeoxycholic acid (TUDCA) has been shown to reduce TTR toxic aggregates in mice [2]. Further, in 2010 Cardoso et al. showed that a combined doxycycline/TUDCA treatment had a synergistic effect, decreasing ATTR deposition. Ursodeoxycholic acid (UDCA) is a bile acid used for the treatment of certain cholestatic syndromes with an efficacy similar to that of TUDCA. Based on this knowledge, we wanted to explore if treatment with doxycycline and UDCA (Dox/Urso) would prevent disease progression in ATTR amyloidosis. UDCA was selected since TUDCA is not available in Sweden.

  • 26.
    Wixner, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Ihse, Elisabet
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    The Swedish open-label diflunisal trial (DFNS01) on hereditary transthyretin amyloidosis and the impact of amyloid fibril composition2019In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 26, p. 39-40Article in journal (Refereed)
    Download full text (pdf)
    fulltext
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