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Population-based studies of atrial fibrillation and ischemic stroke

Berntsson, John LU (2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Abstract
Background: Atrial fibrillation (AF) is a major risk factor for ischemic stroke and the most common cause of cardioembolic stroke. Early detection of AF and AF subjects at high risk for stroke is therefore important. Beyond traditional strong risk factors, such as high age and hypertension, the improvement of risk prediction with existing risk scores, is modest for most other risk markers. Our aim was to study potential risk markers for AF and ischemic stroke in the general population.
Methods: First, natriuretic peptides representing elevated filling pressures, specifically N-terminal pro-B-type natriuretic peptide (NT-proBNP) and Midregional pro-atrial natriuretic peptide (MR-proANP), were studied for association with... (More)
Abstract
Background: Atrial fibrillation (AF) is a major risk factor for ischemic stroke and the most common cause of cardioembolic stroke. Early detection of AF and AF subjects at high risk for stroke is therefore important. Beyond traditional strong risk factors, such as high age and hypertension, the improvement of risk prediction with existing risk scores, is modest for most other risk markers. Our aim was to study potential risk markers for AF and ischemic stroke in the general population.
Methods: First, natriuretic peptides representing elevated filling pressures, specifically N-terminal pro-B-type natriuretic peptide (NT-proBNP) and Midregional pro-atrial natriuretic peptide (MR-proANP), were studied for association with ischemic stroke and ischemic stroke subtypes in 4,862 individuals from the general population (227 ischemic stroke events). Second, MR-proANP was also studied in another 5,130 individuals from the general population in relation to AF (362 AF cases) and stroke (195 cases, of which 158 were ischemic). Third, we investigated whether a newer marker of elevated filling pressures, vascular endothelial growth factor-D (VEGF-D), was associated with AF and ischemic stroke in 4,689 individuals from the general population. Fourth, the risk of ischemic stroke was studied in relation to having a sibling affected by ischemic stroke or AF in a register-based nationwide study of 114,000 AF patients. Finally, we comprehensively searched for novel circulating protein biomarkers for AF through analysis of 1,305 plasma proteins in 757 individuals (226 cases) from the general population in a case-cohort study.
Results: Individuals with high levels of NT-proBNP or MR-proANP had a markedly increased risk of cardioembolic stroke. In addition, MR-proANP and VEGF-D was associated with an increased risk of AF and MR-proANP significantly improved predictive accuracy for AF beyond an established risk score (c-statistic increase from 0.69 to 0.75). In AF patients, a stroke event in a sibling increased the risk of ischemic stroke with a hazard ratio of 1.3 (95% confidence interval, 1.2-1.4). From the 1,305 plasma proteins, five proteins were significantly associated with AF after adjustments for established risk factors. Of those, the associations of NT-proBNP and Tenascin with AF were replicated in an independent cohort.
Conclusions: In this thesis, we confirm previous findings that natriuretic peptides contribute to predictive accuracy of AF and AF-associated ischemic stroke. We also observed increased risk of ischemic stroke in individuals with AF with a sibling affected by ischemic stroke and that high levels of VEGF-D and Tenascin, were associated with an increased AF risk although the contribution to predictive accuracy was limited. Our findings from comprehensive assessment of heritable and circulating factors thus do not support the presence of stronger predictive factors than natriuretic peptides. (Less)
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author
supervisor
opponent
  • professor Løchen, Maja-Lisa, UiT The Arctic University of Norway
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Atrial fibrillation, Ischemic stroke, Biomarker, Stroke, Natriuretic peptides, Vascular endothelial growth factor, Epidemiology, Atrial Fibrillation, Stroke, Ischemic stroke, Natriuretic peptides, Vascular endothelial growth factor, Epidemiology
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2020:17
pages
105 pages
publisher
Lund University, Faculty of Medicine
defense location
Agardh föreläsningssal, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
defense date
2020-03-13 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-877-3
language
English
LU publication?
yes
id
db2630c9-d2b5-4a7b-8ce9-aaf0cd3a87be
date added to LUP
2020-02-20 23:27:40
date last changed
2020-02-21 12:32:51
@phdthesis{db2630c9-d2b5-4a7b-8ce9-aaf0cd3a87be,
  abstract     = {Abstract<br/>Background: Atrial fibrillation (AF) is a major risk factor for ischemic stroke and the most common cause of cardioembolic stroke. Early detection of AF and AF subjects at high risk for stroke is therefore important. Beyond traditional strong risk factors, such as high age and hypertension, the improvement of risk prediction with existing risk scores, is modest for most other risk markers. Our aim was to study potential risk markers for AF and ischemic stroke in the general population.<br/>Methods: First, natriuretic peptides representing elevated filling pressures, specifically N-terminal pro-B-type natriuretic peptide (NT-proBNP) and Midregional pro-atrial natriuretic peptide (MR-proANP), were studied for association with ischemic stroke and ischemic stroke subtypes in 4,862 individuals from the general population (227 ischemic stroke events). Second, MR-proANP was also studied in another  5,130 individuals from the general population in relation to AF (362 AF cases) and stroke (195 cases, of which 158 were ischemic). Third, we investigated whether a newer marker of elevated filling pressures, vascular endothelial growth factor-D (VEGF-D), was associated with AF and ischemic stroke in 4,689 individuals from the general population. Fourth, the risk of ischemic stroke was studied in relation to having a sibling affected by ischemic stroke or AF in a register-based nationwide study of 114,000 AF patients. Finally, we comprehensively searched for novel circulating protein biomarkers for AF through analysis of 1,305 plasma proteins in 757 individuals (226 cases) from the general population in a case-cohort study.<br/>Results: Individuals with high levels of NT-proBNP or MR-proANP had a markedly increased risk of cardioembolic stroke. In addition, MR-proANP and VEGF-D was associated with an increased risk of AF and MR-proANP significantly improved predictive accuracy for AF beyond an established risk score (c-statistic increase from 0.69 to 0.75). In AF patients, a stroke event in a sibling increased the risk of ischemic stroke with a hazard ratio of 1.3 (95% confidence interval, 1.2-1.4). From the 1,305 plasma proteins, five proteins were significantly associated with AF after adjustments for established risk factors. Of those, the associations of NT-proBNP and Tenascin with AF were replicated in an independent cohort.<br/>Conclusions: In this thesis, we confirm previous findings that natriuretic peptides contribute to predictive accuracy of AF and AF-associated ischemic stroke. We also observed increased risk of ischemic stroke in individuals with AF with a sibling affected by ischemic stroke and that high levels of VEGF-D and Tenascin, were associated with an increased AF risk although the contribution to predictive accuracy was limited. Our findings from comprehensive assessment of heritable and circulating factors thus do not support the presence of stronger predictive factors than natriuretic peptides.},
  author       = {Berntsson, John},
  isbn         = {978-91-7619-877-3},
  issn         = {1652-8220},
  language     = {eng},
  number       = {2020:17},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Population-based studies of atrial fibrillation and ischemic stroke},
  year         = {2020},
}