| 1. |
- Ntalla, Ioanna, et al.
(author)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 2. |
- Surendran, Praveen, et al.
(author)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Journal article (peer-reviewed)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 3. |
- Calais, Fredrik, 1971-
(author)
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Coronary artery disease and prognosis in relation to cardiovascular risk factors, interventional techniques and systemic atherosclerosis
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Aim: To evaluate the prognosis associated with location and severity of coronary and systemic atherosclerosis in patients with coronary artery disease (CAD) in relation to risk factors and interventional techniques.Methods: The thesis comprised six longitudinal studies based on three patient cohorts: The Swedish Coronary Angiography and Angioplasty Registry, the Västmanland Myocardial Infarction Survey, and the Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia study, to evaluate clinical outcome relative to coronary lesion location and severity, extracoronary artery disease (ECAD), intervention techniques, and leisuretime physical inactivity (LTPI).Results: Stent placement in the proximal left anterior descending artery (LAD) was more often associated with restenosis than was stenting in the other coronary arteries. The use of drug-eluting stents in the LAD was associated with a lower risk of restenosis and death compared to baremetal stents. Thrombus aspiration in in the LAD during acute ST elevation myocardial infarction (MI) did not improve clinical outcome, irrespective of adjunct intervention technique. Clinical, but not subclinical, ECAD was associated with poor prognosis in patients with MI. Longitudinal extent of CAD at the time of MI was a predictor of ECAD, and coexistence of extensive CAD and ECAD was associated with particularly poor prognosis following MI. Self-reported LTPI was associated with MI and all-cause mortality independent of ECAD.Conclusions: Drug-eluting stents, but not thrombus aspiration, improved prognosis following percutaneous coronary intervention in the proximal LAD. Self- reported LTPI, clinical ECAD, and systemic atherosclerosis defined groups with poor prognosis after MI.
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| 4. |
- Folkersen, Lasse, et al.
(author)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Journal article (peer-reviewed)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 5. |
- Grauman, Åsa, 1982-
(author)
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The publics’ perspective on cardiovascular risk information : Implications for practice
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Lay people struggle to understand the implications of cardiovascular risk information. With new advanced testing techniques and the digitalization of personal health information, the communication of cardiovascular risk becomes a challenge. The overall aim of the thesis was to investigate the publics’ perspective of cardiovascular risk information through a multi-method approach, including how individuals perceive risk, factors affecting an underestimation of risk, how cardiovascular risk communication affects individuals’ psychosocial health, and their preferences for risk communication. In study I, research participants’ perceptions about risk information were explored in five focus group interviews. The participants’ (n=31) perceptions about cardiovascular risk were complex, where multifactorial aspects were disregarded. The communication of cardiovascular risk information did not meet the participants’ need for understanding, support, and guidance regarding what to do with this information. Study II was a before-after investigation regarding the impact of cardiovascular risk information on research participants’ health-related quality of life and mental distress. Increased worry and anxiety were observed in individuals referred to hospital because of coronary artery stenosis. Study III was a cross-sectional study, which found that individuals with a very good or excellent self-perceived general health and individuals without a family history of CVD were more likely to underestimate their cardiovascular risk compared to participants with poor or fairly good general health and without a family history. Study IV was a cross-sectional study, investigating the preferences of the Swedish population for communication of cardiovascular risk information from a health checkup using a Discrete Choice Experiment. Besides cost, consultation time was the most important aspect when communicating cardiovascular risk. The findings suggest that cardiovascular risk communication does not reach its fullest potential when it comes to recipients’ perspective of the benefits of CV risk communication. Improvements should aim at increasing the recipients’ personal control and health literacy and furthermore, acknowledge the fact that self-perceived risk is influenced by how a person feels in general and experiences of family history.
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| 6. |
- Lagedal, Rickard, 1981-
(author)
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Coronary angiography after out-of-hospital cardiac arrest
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Out-of-hospital cardiac arrest (OHCA) is a common cause of death with a survival rate of 10% in Sweden. The chance of survival depends on rapid recognition, high quality cardiopulmonary resuscitation and post-resuscitation care including searching and treating the cause of the arrest. Ischaemic cardiac disease including acute coronary artery occlusions is the most common cause of OHCA. Acute coronary artery lesions can be diagnosed and treated with coronary angiography and subsequent PCI. This thesis analyses various aspects of coronary angiography after OHCA. Paper I+II describes the rational, protocol and the results from the pilot phase (n=117) of a randomized multicentre clinical trial. We compared a strategy of immediate coronary angiography in patients successfully resuscitated after OHCA with a strategy without immediate coronary angiography. We did not reach the stipulated time of 120 minutes from first medical contact to angiography, but our study strategy was feasible. No major unexpected safety issues were reported. The main phase of the study could therefore be started with only minor changes from the pilot phase protocol. In a registry study of 1133 patients (Paper III) coronary angiographic findings were compared with ECG and comorbidities in unconscious patients after OHCA. In patients without ST-elevation, the rate of PCI attempts was higher in patients with ST-depression (47%) and in patients with ECG classified as “other findings” (45%) compared to patients with normal ECG (33%), OR 1.78 (CI 1.13-2.82) and OR 1.65 (CI 1.04-2.61), respectively. When analysing patients without ST-elevation, no difference in PCI rates were found between the comorbidity groups and neither between patients with shockable compared to non-shockable initial ECG rhythm. Paper IV is a registry study (n=3906) analysing the impact of patient income on the probability to receive early coronary angiography after OHCA. When dividing patients into income quarters and adjusting for confounders, increasing income was associated with higher rates of early coronary angiography. Thirty-six percent of patients in the highest income quarter received early angiography compared to fifteen percent in the lowest income quarter, OR 1.64 (1.27-2.11). Adding potential mediators to explain this finding gradually decreased the difference, and the main explanatory factor for this difference was that higher income is associated with higher rates of shockable ECG rhythm. 30-day survival was also higher in the highest income quarter compared to the lowest income group in the fully adjusted analysis, OR 1.51 (CI 1.22-1.89).
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| 7. |
- Lindholm, Daniel, 1982-
(author)
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Platelet Inhibition, Revascularization, and Risk Prediction in Non-ST-elevation Acute Coronary Syndromes
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Cardiovascular disease is the leading cause of death worldwide and ischemic heart disease is the most common manifestation. Despite improved outcomes during the last decades, patients with acute coronary syndromes (ACS) are still at substantial risk of recurrent ischemic events and mortality.The aims of this thesis were to investigate the effect of the novel antiplatelet agent ticagrelor versus clopidogrel in patients with non-ST-elevation ACS (NSTE-ACS), overall and in relation to initial revascularization, and to explore this effect in relation to cardiac biomarkers. The impact of timing of revascularization in non-ST-elevation myocardial infarction (NSTEMI) was also studied, by assessing risk of mortality and recurrent myocardial infarction in relation to delay of percutaneous coronary intervention (PCI) in a nation-wide cohort. Finally, a novel clinical prediction model based on angiographic findings, biomarkers, and clinical characteristics was developed to estimate risk of ischemic events after performed revascularization.Ticagrelor treatment compared with clopidogrel was associated with a reduction in the composite endpoint of cardiovascular death/myocardial infarction/stroke and mortality alone, without any increase in overall major bleeding, but increased non-CABG-related major bleeding. The effect of ticagrelor over clopidogrel was consistent independent of initial revascularization. Elevated high-sensitivity cardiac troponin-T predicted benefit of ticagrelor over clopidogrel, while no difference between treatments was detected at normal levels. In patients with NSTEMI, PCI treatment within two days after hospital admission was associated with lower risk of all-cause death and recurrent myocardial infarction compared with delayed PCI. The new clinical prediction model included the following variables: prior vascular disease, extent of coronary artery disease, level of N-terminal pro-B-type natriuretic peptide and estimated glomerular filtration rate; and showed good discriminatory ability for the risk prediction of cardiovascular death/myocardial infarction/stroke and cardiovascular death alone.In conclusion, these results show that ticagrelor reduces the risk of recurrent ischemic events and mortality in patients with NSTE-ACS when compared with clopidogrel, and this effect seems independent of performed revascularization. The results also indicate that biomarkers could be used to select patients who would benefit most from more intense platelet inhibition. Furthermore, early PCI in NSTEMI seems to be associated with improved outcome. Finally, the novel clinical prediction model based only on four variables showed good discriminatory ability, which makes it a potentially effective and simple tool for tailored treatment based on individual risk of recurrent events.
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| 8. |
- van de Vegte, Yordi, et al.
(author)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 9. |
- Bergström, Göran, 1964, et al.
(author)
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Body weight at age 20 and in midlife is more important than weight gain for coronary atherosclerosis: Results from SCAPIS.
- 2023
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In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 373, s. 46-54
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Journal article (peer-reviewed)abstract
- Elevated body weight in adolescence is associated with early cardiovascular disease, but whether this association is traceable to weight in early adulthood, weight in midlife or to weight gain is not known. The aim of this study is to assess the risk of midlife coronary atherosclerosis being associated with body weight at age 20, body weight in midlife and body weight change.We used data from 25,181 participants with no previous myocardial infarction or cardiac procedure in the Swedish CArdioPulmonary bioImage Study (SCAPIS, mean age 57 years, 51% women). Data on coronary atherosclerosis, self-reported body weight at age 20 and measured midlife weight were recorded together with potential confounders and mediators. Coronary atherosclerosis was assessed using coronary computed tomography angiography (CCTA) and expressed as segment involvement score (SIS).The probability of having coronary atherosclerosis was markedly higher with increasing weight at age 20 and with mid-life weight (p<0.001 for both sexes). However, weight increase from age 20 until mid-life was only modestly associated with coronary atherosclerosis. The association between weight gain and coronary atherosclerosis was mainly seen in men. However, no significant sex difference could be detected when adjusting for the 10-year delay in disease development in women.Similar in men and women, weight at age 20 and weight in midlife are strongly related to coronary atherosclerosis while weight increase from age 20 until midlife is only modestly related to coronary atherosclerosis.
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| 10. |
- Bixby, H., et al.
(author)
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Rising rural body-mass index is the main driver of the global obesity epidemic in adults
- 2019
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 569:7755, s. 260-4
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Journal article (peer-reviewed)abstract
- Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.
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