| 1. |
- Roselli, Carolina, et al.
(författare)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 4. |
- Arvidsson, Per M, et al.
(författare)
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Hemodynamic force analysis is not ready for clinical trials on HFpEF
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Hemodynamic force analysis has been proposed as a novel tool for early detection of subclinical systolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Here we investigated the ability of hemodynamic forces to discriminate between healthy subjects and heart failure patients with varying degrees of systolic dysfunction. We studied 34 controls, 16 HFpEF patients, and 25 heart failure patients with mid-range (HFmrEF) or reduced ejection fraction (HFrEF) using cardiac magnetic resonance with acquisition of cine images and 4D flow at 1.5 T. The Navier-Stokes equation was used to compute global left ventricular hemodynamic forces over the entire cardiac cycle. Forces were analyzed for systole, diastole, and the entire heartbeat, with and without normalization to left ventricular volume. Volume-normalized hemodynamic forces demonstrated significant positive correlation with EF (r2 = 0.47, p < 0.0001) and were found significantly lower in heart failure with reduced ejection fraction compared to controls (p < 0.0001 for systole and diastole). No difference was seen between controls and HFpEF (p > 0.34). Non-normalized forces displayed no differences between controls and HFpEF (p > 0.24 for all analyses) and did not correlate with EF (p = 0.36). Left ventricular hemodynamic force analysis, whether indexed to LV volumes or not, is not ready for clinical trials on HFpEF assessment.
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| 5. |
- Arvidsson, Per Martin, et al.
(författare)
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Kinetic energy of left ventricular blood flow across heart failure phenotypes and in subclinical diastolic dysfunction
- 2022
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Ingår i: Journal of Applied Physiology. - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 133:3, s. 697-709
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Kinetic energy (KE) of intracardiac blood flow reflects myocardial work spent on accelerating blood and provides a mechanistic window into diastolic filling dynamics. Diastolic dysfunction may represent an early stage in the development of heart failure (HF). Here we evaluated the hemodynamic effects of impaired diastolic function in subjects with and without HF, testing the hypothesis that left ventricular KE differs between controls, subjects with subclinical diastolic dysfunction (SDD), and HF patients.METHODS: We studied 77 subjects (16 controls, 20 subjects with SDD, 16 HFpEF, 9 HFmrEF, and 16 HFrEF patients, age- and sex-matched at the group level). Cardiac magnetic resonance at 1.5T included intracardiac 4D flow and cine imaging. Left ventricular KE was calculated as 0.5*m*v 2. RESULTS: Systolic KE was similar between groups (p>0.4), also after indexing to stroke volume (p=0.25), and was primarily driven by ventricular emptying rate (p<0.0001, R 2=0.52). Diastolic KE was higher in heart failure patients than controls (p<0.05) but similar between SDD and HFpEF (p>0.18), correlating with inflow conditions (E-wave velocity, p<0.0001, R 2=0.24) and end-diastolic volume (p=0.0003, R 2=0.17) but not with average e' (p=0.07). CONCLUSIONS: Diastolic KE differs between controls and heart failure, suggesting more work is spent filling the failing ventricle, while systolic KE does not differentiate between well-matched groups with normal ejection fraction even in the presence of relaxation abnormalities and heart failure. Mechanistically, KE reflects the acceleration imparted on the blood and is driven by variations in ventricular emptying and filling rates, volumes, and heart rate, regardless of underlying pathology.
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| 6. |
- Arvidsson, Per Martin, et al.
(författare)
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Kinetic energy of left ventricular blood flow across heart failure phenotypes and in subclinical diastolic dysfunction.
- 2022
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Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - : American Physiological Society. - 1522-1601.
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Tidskriftsartikel (refereegranskat)abstract
- Kinetic energy (KE) of intracardiac blood flow reflects myocardial work spent on accelerating blood and provides a mechanistic window into diastolic filling dynamics. Diastolic dysfunction may represent an early stage in the development of heart failure (HF). Here we evaluated the hemodynamic effects of impaired diastolic function in subjects with and without HF, testing the hypothesis that left ventricular KE differs between controls, subjects with subclinical diastolic dysfunction (SDD), and HF patients.We studied 77 subjects (16 controls, 20 subjects with SDD, 16 HFpEF, 9 HFmrEF, and 16 HFrEF patients, age- and sex-matched at the group level). Cardiac magnetic resonance at 1.5T included intracardiac 4D flow and cine imaging. Left ventricular KE was calculated as 0.5*m*v2.Systolic KE was similar between groups (p>0.4), also after indexing to stroke volume (p=0.25), and was primarily driven by ventricular emptying rate (p<0.0001, R2=0.52). Diastolic KE was higher in heart failure patients than controls (p<0.05) but similar between SDD and HFpEF (p>0.18), correlating with inflow conditions (E-wave velocity, p<0.0001, R2=0.24) and end-diastolic volume (p=0.0003, R2=0.17) but not with average e' (p=0.07).Diastolic KE differs between controls and heart failure, suggesting more work is spent filling the failing ventricle, while systolic KE does not differentiate between well-matched groups with normal ejection fraction even in the presence of relaxation abnormalities and heart failure. Mechanistically, KE reflects the acceleration imparted on the blood and is driven by variations in ventricular emptying and filling rates, volumes, and heart rate, regardless of underlying pathology.
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| 7. |
- Edlund, Jonathan, et al.
(författare)
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Noninvasive Assessment of Left Ventricular Pressure-Volume Relations : Inter- and Intraobserver Variability and Assessment Across Heart Failure Subtypes
- 2022
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 1879-1913 .- 0002-9149. ; 184, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- A novel method to derive pressure-volume (PV) loops noninvasively from cardiac magnetic resonance images has recently been developed. The aim of this study was to evaluate inter- and intraobserver variability of hemodynamic parameters obtained from noninvasive PV loops in healthy controls, subclinical diastolic dysfunction (SDD), and patients with heart failure with preserved ejection fraction, mildly reduced ejection fraction, and reduced ejection fraction. We included 75 subjects, of whom 15 were healthy controls, 15 subjects with SDD (defined as fulfilling 1 to 2 echocardiographic criteria for diastolic dysfunction), and 15 patients with preserved ejection fraction, 15 with mildly reduced ejection fraction, and 15 with reduced ejection fraction. PV loops were computed using time-resolved left ventricular volumes from cardiac magnetic resonance images and a brachial blood pressure. Inter- and intraobserver variability and intergroup differences of PV loop-derived hemodynamic parameters were assessed. Bias was low and limits of agreement were narrow for all hemodynamic parameters in the inter- and intraobserver comparisons. Interobserver difference for stroke work was 2 ± 9%, potential energy was 4 ± 11%, and maximal ventricular elastance was -4 ± 7%. Intraobserver for stroke work was -1 ± 7%, potential energy was 3 ± 4%, and maximal ventricular elastance was 1 ± 5%. In conclusion, this study presents a fully noninvasive left ventricular PV loop analysis across healthy controls, subjects with SDD, and patients with heart failure with preserved or impaired systolic function. In conclusion, the method for PV loop computation from clinical-standard manual left ventricular segmentation was rapid and robust, bridging the gap between clinical and research settings.
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| 8. |
- Edlund, Jonathan, et al.
(författare)
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Noninvasive Assessment of Left Ventricular Pressure-Volume Relations: Inter- and Intraobserver Variability and Assessment Across Heart Failure Subtypes.
- 2022
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Ingår i: The American journal of cardiology. - : Elsevier BV. - 1879-1913 .- 0002-9149.
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Tidskriftsartikel (refereegranskat)abstract
- A novel method to derive pressure-volume (PV) loops noninvasively from cardiac magnetic resonance images has recently been developed. The aim of this study was to evaluate inter- and intraobserver variability of hemodynamic parameters obtained from noninvasive PV loops in healthy controls, subclinical diastolic dysfunction (SDD), and patients with heart failure with preserved ejection fraction, mildly reduced ejection fraction, and reduced ejection fraction. We included 75 subjects, of whom 15 were healthy controls, 15 subjects with SDD (defined as fulfilling 1 to 2 echocardiographic criteria for diastolic dysfunction), and 15 patients with preserved ejection fraction, 15 with mildly reduced ejection fraction, and 15 with reduced ejection fraction. PV loops were computed using time-resolved left ventricular volumes from cardiac magnetic resonance images and a brachial blood pressure. Inter- and intraobserver variability and intergroup differences of PV loop-derived hemodynamic parameters were assessed. Bias was low and limits of agreement were narrow for all hemodynamic parameters in the inter- and intraobserver comparisons. Interobserver difference for stroke work was 2 ± 9%, potential energy was 4 ± 11%, and maximal ventricular elastance was -4 ± 7%. Intraobserver for stroke work was -1 ± 7%, potential energy was 3 ± 4%, and maximal ventricular elastance was 1 ± 5%. In conclusion, this study presents a fully noninvasive left ventricular PV loop analysis across healthy controls, subjects with SDD, and patients with heart failure with preserved or impaired systolic function. In conclusion, the method for PV loop computation from clinical-standard manual left ventricular segmentation was rapid and robust, bridging the gap between clinical and research settings.
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| 9. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 10. |
- Leopoulou, Marianna, et al.
(författare)
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Naxos disease – a narrative review
- 2020
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Ingår i: Expert Review of Cardiovascular Therapy. - : Taylor & Francis. - 1477-9072 .- 1744-8344. ; 18:11, s. 801-808
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionNaxos disease is a rare entity that manifests with woolly hair, keratosis of extremities, and cardiac manifestations that resemble arrhythmogenic right ventricular cardiomyopathy. It is inherited in an autosomal recessive pattern and mutations affecting plakoglobin and desmoplakin have been identified. There is an increased risk of arrhythmias, including sudden cardiac death at a young age. Right ventricular systolic dysfunction often progresses and left ventricular involvement may also occur.Areas coveredThis article reviews historic background, epidemiology, clinical characteristics, genetics, and pathogenesis as well as therapeutic management and future perspectives.Expert opinionThe principles of evaluation and treatment are based on arrhythmogenic right ventricular cardiomyopathy (ARVC) and general heart failure guidelines, because specific data on Naxos disease are limited. Therefore, larger registries on Naxos disease are welcome in order to gain more knowledge about clinical course and risk stratification. Translational research on pathophysiological mechanisms has evolved, including promising approaches using stem cells for novel targets.
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