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Novel and Traditional Risk Factors for Coronary Artery Disease: Role of Coronary Artery Calcium, Lipidomics, Psychosocial Factors and Diet
Örebro University, School of Medical Sciences.ORCID iD: 0000-0002-2957-9904
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: The aim of the research reported in this thesis was to determine the association of novel and traditional risk factors with coronary artery calcium (CAC), a marker of subclinical coronary artery disease (CAD) in healthy individuals. In addition, we investigated the effects of a vegetarian, compared to a meat diet, on novel and traditional risk factors in patients with diagnosed CAD.

Methods: Studies I-II evaluated the inter-laboratory reproducibility of liquid chromatography-mass spectrometry (LC-MS) lipid analysis and the association of serum lipidome with CAC in a cohort of 70 patients. Studies III and IV analysed data of 1067 participants in the pilot study of the Swedish CArdioPulmonary bioImage Study to determine associations of psychosocial (residential area, education, housing, and social support) and traditional risk factors with CAC. Cardiac computed tomography was used to obtain a coronary artery calcium score (CACS) (Studies I–IV). Study V employed a crossover design in which 31 patients with CAD were randomly allocated to a four-week vegetarian diet alternating with four weeks of an isocaloric meat diet. Enzyme-linked immunosorbent assay was used to measure oxidised LDL-cholesterol. Plasma metabolome, including choline, trimethylamine N-oxide, L-carnitine, and acetyl-carnitine, as well as plasma lipidome were determined with LC-MS. Gut microbiota and faecal short- and branched-chain fatty acids were analysed with 16S rRNA gene sequencing and gas chromatography-MS, respectively.

Results: In Study I, two laboratories independently identified six lipids in common that differentiated serum of patients with CACS >250 from that of those with CACS=0. Study II, revealed higher levels of phosphatidylcholine(PC)(16:0/20:4) and lower levels of PC(18:2/18:2), PC(36:3) and phosphatidylethanolamine (PE)(20:0/18:2) in patients with CACS >250 than found in those with CACS=0. Study III showed a CACS >0 prevalence of 46.3% and 36.6% in low and high socioeconomic residential areas, respectively, but the traditional risk factor–adjusted odds ratio for CACS >0 was not significantly higher in subjects living in low socioeconomic areas. In Study III, the traditional risk factor–adjusted odds ratio for CACS >100 relative to CACS=0 was significantly higher in women with low education level and living in a rented apartment. Studies III and IV showed traditional risk factor–adjusted odds ratios for CACS >0 to be significantly higher in women with a family history of premature cardiovascular disease and low social support. No relationship of psychosocial factors with CAC was observed in men. The vegetarian diet implemented in Study V significantly lowered mean oxidized LDL-cholesterol (-2.73 U/L), total cholesterol (-0.13 mmol/L), LDL-cholesterol (-0.10 mmol/L), and body mass index (-0.21 kg/m2), as well as the relative abundance of PCs, PEs, and several microbial genera compared with the meat diet. The effect of the vegetarian diet on oxidized LDL-C was associated with higher relative abundance of Ruminococcaceae genera and of Barnesiella and reduced abundance of Flavonifractor. The vegetarian diet lowered the relative abundance of ceramide(d18:1/16:0) and triacylglycerols with saturated fatty acyl chains and raised the relative abundance of triacylglycerols with high carbon and polyunsaturated fatty acyl chains compared with the meat diet.

Conclusions: Novel and traditional cardiovascular risk factors are associated with subclinical CAD. Psychosocial factors are associated with subclinical CAD in women, but not in men. Short-term intervention with a vegetarian diet in individuals with CAD can positively impact novel and traditional factors that have been associated with risk of future cardiovascular events.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2020. , p. 85
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 215
Keywords [en]
Novel risk factors, coronary artery calcium, lipidomics, lipidome, psychosocial factors, vegetarian diet, gut microbiota, metabolome
National Category
General Practice Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:oru:diva-80920ISBN: 978-91-7529-342-4 (print)OAI: oai:DiVA.org:oru-80920DiVA, id: diva2:1420620
Public defence
2020-06-12, Örebro universitet, Campus USÖ, hörsal C1, Södra Grev Rosengatan 32, Örebro, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2020-03-31 Created: 2020-03-31 Last updated: 2020-05-19Bibliographically approved
List of papers
1. Replication of LC-MS untargeted lipidomics results in patients with calcific coronary disease: an interlaboratory reproducibility study
Open this publication in new window or tab >>Replication of LC-MS untargeted lipidomics results in patients with calcific coronary disease: an interlaboratory reproducibility study
2016 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 222, p. 1042-1048Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Recently a lipidomics approach was able to identify perturbed fatty acyl chain (FAC) and sphingolipid moieties that could stratify patients according to the severity of coronary calcification, a form of subclinical atherosclerosis. Nevertheless, these findings have not yet been reproduced before generalising their application. The aim of this study was to evaluate the reproducibility of lipidomics approaches by replicating previous lipidomic findings in groups of patients with calcific coronary artery disease (CCAD).

METHODS: Patients were separated into the following groups based on their calcium score (CS); no calcification (CS: 0; n=26), mild calcification (CS: 1-250; n=27) and severe calcification (CS: >250; n=17). Two serum samples were collected from each patient and used for comparative analyses by 2 different laboratories, in different countries and time points using liquid chromatography coupled to mass spectrometry untargeted lipidomics methods.

RESULTS: Six identical metabolites differentiated patients with severe coronary artery calcification from those with no calcification were found by both laboratories independently. Additionally, relative intensities from the two analyses demonstrated high correlation coefficients. Phosphatidylcholine moieties with 18-carbon FAC were identified in lower intensities and 20:4 FAC in higher intensities in the serum of diseased group. Moreover, 3 common sphingomyelins were detected.

CONCLUSION: This is the first interlaboratory reproducibility study utilising lipidomics applications in general and specifically in patients with CCAD. Lipid profiling applications in patients with CCAD are very reproducible in highly specialised and experienced laboratories and could be applied in clinical practice in order to spare patients diagnostic radiation.

Place, publisher, year, edition, pages
Elsevier, 2016
Keywords
Lipidomics, Reproducibility, Coronary artery disease, Calcific coronary disease, Metabolomics
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:oru:diva-57882 (URN)10.1016/j.ijcard.2016.07.214 (DOI)000384698300219 ()27543723 (PubMedID)2-s2.0-84982192130 (Scopus ID)
Funder
Swedish Heart Lung Foundation
Available from: 2016-10-24 Created: 2017-06-01 Last updated: 2020-05-19Bibliographically approved
2. Serum untargeted lipidomic profiling reveals dysfunction of phospholipid metabolism in subclinical coronary artery disease
Open this publication in new window or tab >>Serum untargeted lipidomic profiling reveals dysfunction of phospholipid metabolism in subclinical coronary artery disease
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2019 (English)In: Vascular Health and Risk Management, ISSN 1176-6344, E-ISSN 1178-2048, Vol. 15, p. 123-135Article in journal (Refereed) Published
Abstract [en]

Purpose: Disturbed metabolism of cholesterol and triacylglycerols (TGs) carries increased risk for coronary artery calcification (CAC). However, the exact relationship between individual lipid species and CAC remains unclear. The aim of this study was to identify disturbances in lipid profiles involved in the calcification process, in an attempt to propose potential biomarker candidates.

Patients and methods: We studied 70 patients at intermediate risk for coronary artery disease who had undergone coronary calcification assessment using computed tomography and Agatston coronary artery calcium score (CACS). Patients were divided into three groups: with no coronary calcification (NCC; CACS: 0; n=26), mild coronary calcification (MCC; CACS: 1-250; n=27), or severe coronary calcification (SCC; CACS: >250; n=17). Patients' serum samples were analyzed using liquid chromatography-mass spectrometry in an untargeted lipidomics approach.

Results: We identified 103 lipids within the glycerolipid, glycerophospholipid, sphingolipid, and sterol lipid classes. After false discovery rate correction, phosphatidylcholine (PC)(16:0/20:4) in higher levels and PC(18:2/18:2), PC(36:3), and phosphatidylethanolamine(20:0/18:2) in lower levels were identified as correlates with SCC compared to NCC. There were no significant differences in the levels of individual TGs between the three groups; however, clustering the lipid profiles showed a trend for higher levels of saturated and monounsaturated TGs in SCC compared to NCC. There was also a trend for lower TG (49:2), TG(51:1), TG(54:5), and TG(56:8) levels in SCC compared to MCC.

Conclusion: In this study we investigated the lipidome of patients with coronary calcification. Our results suggest that the calcification process may be associated with dysfunction in autophagy. The lipidomic biomarkers revealed in this study may aid in better assessment of patients with subclinical coronary artery disease.

Place, publisher, year, edition, pages
DOVE Medical Press Ltd., 2019
Keywords
coronary artery calcification, coronary artery calcium score, lipidomics, triacylglycerol, lipids, atherosclerosis, autophagy
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-74648 (URN)10.2147/VHRM.S202344 (DOI)000468547500001 ()
Funder
Swedish Heart Lung Foundation
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2020-05-19Bibliographically approved
3. Impact of socioeconomic status on coronary artery calcification
Open this publication in new window or tab >>Impact of socioeconomic status on coronary artery calcification
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2018 (English)In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 25, no 16, p. 1756-1764Article in journal (Refereed) Published
Abstract [en]

Background: Low socioeconomic status is associated with an increased risk of coronary artery disease, but few studies have investigated the potential link between living in an area with a low versus a high socioeconomic status and coronary artery calcification, a marker of subclinical coronary artery disease. Design The design of this study was a cross-sectional study. Methods We evaluated 1067 participants with no history of coronary artery disease from the pilot phase of the Swedish CArdioPulmonary bioImage Study (SCAPIS). Men and women aged 50-64 years were recruited from three high-socioeconomic status ( n = 541) and three low-socioeconomic status ( n = 526) areas in the city of Gothenburg (550,000 inhabitants). The coronary artery calcification score was assessed with the Agatston method using computed tomography, with individuals classified into either no coronary calcification ( n = 625; mean age, 57 years) or any coronary artery calcification ( n = 442; mean age, 59 years (men, 68.5%)). Results Coronary artery calcification was present in 244 (46.3%) and 198 (36.6%) individuals from the low- and high-socioeconomic status areas, respectively. Participants from the low-socioeconomic status areas had a significantly higher risk factor burden. In a multivariable logistic regression model with adjustment for age, sex and cardiovascular risk factors, the odds for coronary artery calcification were not significantly higher among persons living in low-socioeconomic status areas (odds ratio = 1.18, 95% confidence interval = 0.87-1.60). Conclusion In this relatively small cross-sectional study, we observed an association between living in a low-socioeconomic status area and coronary artery calcification. However, this was mostly explained by higher levels of cardiovascular disease risk factors, indicating that the effect of socioeconomic status on the atherosclerotic process works through an increased burden of cardiovascular disease risk factors.

Place, publisher, year, edition, pages
Sage Publications, 2018
Keywords
Socioeconomic status, social classes, neighbourhood, coronary artery calcification, subclinical coronary artery disease, ethnic group, nationality
National Category
Public Health, Global Health, Social Medicine and Epidemiology Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-68438 (URN)10.1177/2047487318792103 (DOI)000448077100012 ()30095278 (PubMedID)2-s2.0-85052572798 (Scopus ID)
Funder
Swedish Heart Lung FoundationKnut and Alice Wallenberg FoundationSwedish Research CouncilVINNOVARegion Västra Götaland
Note

Funding Agency:

Sahlgrenska Academy at the University of Gothenburg

Available from: 2018-08-13 Created: 2018-08-13 Last updated: 2020-05-19Bibliographically approved
4. Social Support and Subclinical Coronary Artery Disease in Middle-Aged Men and Women: Findings from the Pilot of Swedish CArdioPulmonary bioImage Study
Open this publication in new window or tab >>Social Support and Subclinical Coronary Artery Disease in Middle-Aged Men and Women: Findings from the Pilot of Swedish CArdioPulmonary bioImage Study
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2020 (English)In: International Journal of Environmental Research and Public Health, ISSN 1661-7827, E-ISSN 1660-4601, Vol. 17, no 3, article id 778Article in journal (Refereed) Published
Abstract [en]

Social support has been associated with coronary artery disease (CAD), particularly in individuals who have sustained a cardiovascular event. This study investigated the relationship between social support and subclinical CAD among 1067 healthy middle-aged men and women. Social support was assessed with validated social integration and emotional attachment measures. Subclinical CAD was assessed as a coronary artery calcium score (CACS) using computed tomography. There was no association between social support and CACS in men. In women, low social support was strongly linked to cardiovascular risk factors, high levels of inflammatory markers, and CACS > 0. In a logistic regression model, after adjustment for 12 cardiovascular risk factors, the odds ratio (95% confidence intervals) for CACS > 0 in women with the lowest social integration, emotional attachment, and social support groups (reference: highest corresponding group) were 2.47 (1.23-5.12), 1.87 (0.93-3.59), and 4.28 (1.52-12.28), respectively. Using a machine learning approach (random forest), social integration was the fourth (out of 12) most important risk factor for CACS > 0 in women. Women with lower compared to higher or moderate social integration levels were about 14 years older in "vascular age". This study showed an association between lack of social support and subclinical CAD in middle-aged women, but not in men. Lack of social support may affect the atherosclerotic process and identify individuals vulnerable to CAD events.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
Social support, women, coronary artery calcium, coronary artery calcification, subclinical coronary artery disease, inflammation
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:oru:diva-80753 (URN)10.3390/ijerph17030778 (DOI)000517783300103 ()32012689 (PubMedID)2-s2.0-85078872171 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilVinnovaRegion Västra GötalandAFA InsuranceSwedish Heart Lung Foundation
Note

Funding Agencies:

Sahlgrenska Academy at University of Gothenburg

Region Örebro County through ALF research fund

Swedish CArdioPulmonary bioImage Study (SCAPIS) is the Swedish Heart and Lung Foundation

Available from: 2020-03-20 Created: 2020-03-20 Last updated: 2020-05-19Bibliographically approved
5. Effects of a vegetarian diet on cardiometabolic risk factors, gut microbiota, and plasma metabolome in subjects with ischemic heart disease - a randomized, cross-over study
Open this publication in new window or tab >>Effects of a vegetarian diet on cardiometabolic risk factors, gut microbiota, and plasma metabolome in subjects with ischemic heart disease - a randomized, cross-over study
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(English)Manuscript (preprint) (Other academic)
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-81939 (URN)
Available from: 2020-05-19 Created: 2020-05-19 Last updated: 2020-05-19Bibliographically approved

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