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Publications (10 of 16) Show all publications
Hansén, N., Ljungberg, J., Bergdahl, I., Hultdin, J., Näslund, U., Johansson, B. & Söderberg, S. (2023). Adipokines are possible risk markers for aortic stenosis requiring surgery. Scandinavian Cardiovascular Journal, 57(1), Article ID 2247193.
Open this publication in new window or tab >>Adipokines are possible risk markers for aortic stenosis requiring surgery
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2023 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 57, no 1, article id 2247193Article in journal (Refereed) Published
Abstract [en]

Objectives: Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR).

Design: In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents.

Results: Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92–1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08–1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82–1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64–0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI).

Conclusions: The adipokine leptin may promote the development of AS.

Place, publisher, year, edition, pages
Taylor & Francis, 2023
Keywords
adiponectin, Aortic stenosis, fat mass, leptin, prospective study, risk markers
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-214075 (URN)10.1080/14017431.2023.2247193 (DOI)001050266400001 ()37592808 (PubMedID)2-s2.0-85168287214 (Scopus ID)
Funder
Swedish Heart Lung Foundation, 20100635Swedish Heart Lung Foundation, 20120631Swedish Heart Lung Foundation, 20140799Swedish Heart Lung Foundation, 20130630Region Västerbotten, RV-967561Umeå University, 964731
Available from: 2023-09-04 Created: 2023-09-04 Last updated: 2023-09-04Bibliographically approved
Yu Chen, H., Dina, C., Small, A. M., Shaffer, C. M., Levinson, R. T., Helgadóttir, A., . . . Thanassoulis, G. (2023). Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study. European Heart Journal, 44(21), 1927-1939
Open this publication in new window or tab >>Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study
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2023 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 44, no 21, p. 1927-1939Article in journal (Refereed) Published
Abstract [en]

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
Aortic stenosis, Gene expression, Genetic risk score, Genome-wide association study, Mendelian randomization, Phenome-wide association study
National Category
Cardiac and Cardiovascular Systems Medical Genetics
Identifiers
urn:nbn:se:umu:diva-209555 (URN)10.1093/eurheartj/ehad142 (DOI)000989753300001 ()37038246 (PubMedID)2-s2.0-85160838840 (Scopus ID)
Funder
Swedish Heart Lung Foundation, 20140799Swedish Heart Lung Foundation, 20120631Swedish Heart Lung Foundation, 20100635Region Västerbotten, VLL-548791Swedish Heart Lung Foundation, 2016-0134Swedish Heart Lung Foundation, 2016-0315Swedish Heart Lung Foundation, 2019-0526Swedish Research Council, 2017-02554Knut and Alice Wallenberg FoundationSwedish Research Council, 349-2006-237Swedish Foundation for Strategic Research, IRC15-0067NIH (National Institutes of Health), R01 HL128550NordForsk, 90580
Available from: 2023-06-12 Created: 2023-06-12 Last updated: 2023-09-05Bibliographically approved
Skoglund Larsson, L., Ljungberg, J., Johansson, L., Carlberg, B., Söderberg, S. & Brunström, M. (2022). Survival after surgery of the ascending aorta: a matched cohort study. European Journal of Cardio-Thoracic Surgery, 62(3)
Open this publication in new window or tab >>Survival after surgery of the ascending aorta: a matched cohort study
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2022 (English)In: European Journal of Cardio-Thoracic Surgery, ISSN 1010-7940, E-ISSN 1873-734X, Vol. 62, no 3Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Surgery of ascending aortic aneurysms is performed prophylactically or acute. The expected survival after surgery is uncertain. The goal of this study was to compare mortality in people with aortic surgery with matched controls.

METHODS: All patients undergoing ascending aortic surgery at Umeå University Hospital from 1988 to 2012, who previously participated in 1 of 3 population-based health surveys, were matched to 2 randomly selected controls from the same health survey and followed until death or until censoring on 24 August 2017, whichever came first. Mortality was calculated using the Kaplan-Meier method and the log-rank test. Cox regression analyses were made for all-cause mortality, adjusted for traditional cardiovascular risk factors. Deaths during the first 90 days after surgery and at >90 days postoperatively were studied separately.

RESULTS: The median follow-up time was 9.2 years. A total of 61 of 189 patients and 51 of 370 controls died [hazard ratio (HR) 2.77, 95% confidence interval (CI) 1.91-4.01]. Mortality was increased during the first 90 days post-surgery (HR 43.4, 95% CI 5.83-323), as well as after the first 90 days (HR 1.90, 95% CI 1.25-2.88) and after acute surgery (HR 6.05, 95% CI 2.92-12.56) as well as after elective surgery (HR 2.10, 95% CI 1.35-3.27). Among 57 surgical patients with information about cause of death, 23 (40%) died of aortic disease.

CONCLUSIONS: During follow-up, more patients died than matched controls. Findings were consistent when adjusting for traditional cardiovascular risk factors and across subgroups. Both short-term and long-term postoperative deaths were increased as well.

Place, publisher, year, edition, pages
Oxford University Press, 2022
Keywords
aortic aneurysm, aortic dissection, surgery, survival, Thoracic aorta
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-200112 (URN)10.1093/ejcts/ezac161 (DOI)000784733900001 ()35394018 (PubMedID)2-s2.0-85138458169 (Scopus ID)
Funder
Region VästerbottenSwedish Heart Lung FoundationKonung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Available from: 2022-10-12 Created: 2022-10-12 Last updated: 2023-05-22Bibliographically approved
Bergström, G., Persson, M., Adiels, M., Björnson, E., Bonander, C., Ahlström, H., . . . Jernberg, T. (2021). Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population. Circulation, 144(12), 916-929
Open this publication in new window or tab >>Prevalence of Subclinical Coronary Artery Atherosclerosis in the General Population
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2021 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 144, no 12, p. 916-929Article in journal (Refereed) Published
Abstract [en]

Background: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population.

Methods: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data.

Results: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population.

Conclusions: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

Place, publisher, year, edition, pages
American Heart Association, 2021
Keywords
coronary angiography, coronary artery disease, epidemiology, plaque, atherosclerotic, primary prevention, tomography
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-187757 (URN)10.1161/CIRCULATIONAHA.121.055340 (DOI)000697544600010 ()34543072 (PubMedID)2-s2.0-85115941267 (Scopus ID)
Funder
Pfizer ABAstraZenecaVinnovaSwedish Heart Lung FoundationKnut and Alice Wallenberg FoundationNovo NordiskRegion StockholmSwedish Research Council
Available from: 2021-09-21 Created: 2021-09-21 Last updated: 2023-05-09Bibliographically approved
Chen, H. Y., Cairns, B. J., Small, A. M., Burr, H. A., Ambikkumar, A., Martinsson, A., . . . Thanassoulis, G. (2020). Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis. JAMA cardiology, 5(6), 694-702
Open this publication in new window or tab >>Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis
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2020 (English)In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 5, no 6, p. 694-702Article in journal (Refereed) Published
Abstract [en]

Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets.

Objective: To identify novel genetic loci and pathways associated with AS.

Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019.

Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples.

Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography.

Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]).

Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.

Place, publisher, year, edition, pages
American Medical Association (AMA), 2020
National Category
Cardiac and Cardiovascular Systems
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-170494 (URN)10.1001/jamacardio.2020.0246 (DOI)000545603400014 ()32186652 (PubMedID)2-s2.0-85082412919 (Scopus ID)
Funder
NIH (National Institute of Health), R01 HL128550NIH (National Institute of Health), HHSN268201500003INIH (National Institute of Health), s10rr025141NIH (National Institute of Health), U01HG004798NIH (National Institute of Health), R01NS032830NIH (National Institute of Health), RC2GM092618NIH (National Institute of Health), P50GM115305NIH (National Institute of Health), U01HG006378NIH (National Institute of Health), U19HL065962NIH (National Institute of Health), R01HD07471NIH (National Institute of Health), N01-HC-95159NIH (National Institute of Health), N01-HC-95160NIH (National Institute of Health), N01-HC-95161NIH (National Institute of Health), N01-HC-95162NIH (National Institute of Health), N01-HC-95163NIH (National Institute of Health), N01-HC-95164NIH (National Institute of Health), N01-HC-95165NIH (National Institute of Health), N01-HC-95166NIH (National Institute of Health), N01-HC-95167NIH (National Institute of Health), N01-HC-95168NIH (National Institute of Health), N01-HC-95169NIH (National Institute of Health), N02-HL-64278NIH (National Institute of Health), UL1-TR-000040NIH (National Institute of Health), UL1-TR-001079NIH (National Institute of Health), UL1-TR-001420NIH (National Institute of Health), UL1-TR-001881NIH (National Institute of Health), UL1TR002243NIH (National Institute of Health), UL1TR000445
Available from: 2020-05-07 Created: 2020-05-07 Last updated: 2023-03-24Bibliographically approved
Holmgren, A., Ljungberg, J., Hultdin, J., Johansson, B., Bergdahl, I., Näslund, U. & Söderberg, S. (2020). Troponin T but not C-reactive protein is associated with future surgery for aortic stenosis: a population based nested case-referent study. Open heart, 7(2), Article ID e001325.
Open this publication in new window or tab >>Troponin T but not C-reactive protein is associated with future surgery for aortic stenosis: a population based nested case-referent study
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2020 (English)In: Open heart, E-ISSN 2053-3624, Vol. 7, no 2, article id e001325Article in journal (Refereed) Published
Abstract [en]

Aims: High-sensitivity troponin T (hs-TnT) and high-sensitivity C reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). This study evaluated if hs-TnT and hs-CRP associate with myocardial mass, and risk of future surgery for AS.

Methods: In total, 336 patients (48% women) with surgery for AS with previous participation in large population surveys were identified. Preoperatively, myocardial mass and the presence of coronary artery disease (CAD) were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma from the baseline survey. Conditional logistic regression analysis was used to estimate the risk (OR (95% CI)) related to one (natural logarithm) SD increase in hs-TnT and hs-CRP. Kaplan-Mayer and Cox regression analyses were used to evaluate time to surgery.

Results: Median age (IQR) was 59.8 (10.3) years at survey, and median time between survey and surgery was 10.9 (9.3) years. Hs-TnT was independently associated with surgery for AS (1.24 (1.06–1.44)) irrespective of CAD, whereas Hs-CRP was not (1.05 (0.90–1.22)). Elevated hs-TnT levels at survey associated with shorter time to surgery (p<0.001), and with increased myocardial mass (p=0.002). Hs-CRP did not associate with time to surgery or with myocardial mass.

Conclusions: Hs-TnT—but not hs-CRP—was associated with increased risk of—and shorter time to—future surgery for AS. Hs-TnT associated with myocardial mass at surgery which indicates that hs-TnT could be a potential biomarker for determining intervention.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2020
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-159019 (URN)10.1136/openhrt-2020-001325 (DOI)000583257500001 ()33051334 (PubMedID)2-s2.0-85093503026 (Scopus ID)
Funder
Swedish Heart Lung Foundation, 20140799Swedish Heart Lung Foundation, 20 120 631Swedish Heart Lung Foundation, 20100635Region Västerbotten, VLL-548791
Note

Previously included in thesis in manuscript form

Available from: 2019-05-16 Created: 2019-05-16 Last updated: 2023-03-24Bibliographically approved
Söderberg, S., Holmgren, A., Ljungberg, J., Hultdin, J., Bergdahl, I., Näslund, U. & Johansson, B. (2020). Troponin T but not C-reactive protein is associated with myocardial mass and risk for, and time to future surgery for aortic stenosis: a population-based study. European Heart Journal, 41, 1884-1884
Open this publication in new window or tab >>Troponin T but not C-reactive protein is associated with myocardial mass and risk for, and time to future surgery for aortic stenosis: a population-based study
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2020 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 41, p. 1884-1884Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2020
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-180149 (URN)10.1093/ehjci/ehaa946.1884 (DOI)000606106301887 ()
Note

Supplement: 2

Available from: 2021-02-18 Created: 2021-02-18 Last updated: 2022-02-14Bibliographically approved
Ljungberg, J., Johansson, B., Engström, K. G., Norberg, M., Bergdahl, I. A. & Söderberg, S. (2019). Arterial hypertension and diastolic blood pressure associate with aortic stenosis. Scandinavian Cardiovascular Journal, 53(2), 91-97
Open this publication in new window or tab >>Arterial hypertension and diastolic blood pressure associate with aortic stenosis
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2019 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 53, no 2, p. 91-97Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis (AS) and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on AS development requiring surgery among patients without concomitant coronary artery disease (CAD) and stratified for age.

DESIGN: This study included 322 patients, who had prior to surgery for AS participated in population-based surveys, and 131 of them had no visible CAD upon preoperative coronary angiogram. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension (or measured blood pressure and antihypertensive medication), cholesterol levels, diabetes, body mass index (BMI), and smoking.

RESULTS: In patients without CAD, future surgery for AS was associated with arterial hypertension and elevated levels of diastolic blood pressure in patients younger than 60 years at surgery (odds ratio [95% confidence interval]), (3.40 [1.45-7.93] and 1.60 [1.09-2.37], respectively), and with only impaired fasting glucose tolerance in patients 60 years or older at surgery (3.22 [1.19-8.76]).

CONCLUSION: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for AS requiring surgery in subjects below 60 years of age. Strict blood pressure control in this group is strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk factors for developing AS requiring surgery need further investigations. Notably, elevated fasting glucose levels were related to AS requiring surgery in older adults without concomitant CAD.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2019
Keywords
Aortic stenosis, bicuspid aortic valve, diabetes, hypertension, valve disease surgery
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-159471 (URN)10.1080/14017431.2019.1605094 (DOI)000469026200007 ()31109205 (PubMedID)2-s2.0-85066399670 (Scopus ID)
Funder
Swedish Heart Lung Foundation, 20140799Swedish Heart Lung Foundation, 20120631Swedish Heart Lung Foundation, 20100635Västerbotten County Council, VLL-548791
Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2023-03-23Bibliographically approved
Ljungberg, J., Johansson, B., Bergdahl, I., Holmgren, A., Näslund, U., Hultdin, J. & Söderberg, S. (2019). Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis. Scandinavian Journal of Clinical and Laboratory Investigation, 79(7), 524-530
Open this publication in new window or tab >>Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis
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2019 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 7, p. 524-530Article in journal (Refereed) Published
Abstract [en]

Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFR(cystatin C) and eGFR(creatinine) and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFR(cystatin C) and eGFR(creatinine). A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFR(cystatin C) and eGFR(creatinine) was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Aortic stenosis, valvular replacement, renal insufficiency, creatinine, cystatin C
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-164404 (URN)10.1080/00365513.2019.1664761 (DOI)000486559100001 ()31522562 (PubMedID)2-s2.0-85073124103 (Scopus ID)
Available from: 2019-11-05 Created: 2019-11-05 Last updated: 2023-03-24Bibliographically approved
Ljungberg, J. (2018). Cardiovascular risk factors in aortic stenosis. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Cardiovascular risk factors in aortic stenosis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Kardiovaskulära riskfaktorer vid aortastenos
Abstract [en]

Introduction: Aortic stenosis (AS) is the most common hemodynamic significant valvular heart disease and affects about 2% of the population. The incidence increases with age. When symptoms of the stenotic aortic valve disease eventually occur the 2-year mortality exceeds 50%. Aortic valve replacement (AVR) by surgery or by catheter intervention is the only known treatment. The causes of AS are only partly known, despite that the disease has been known since the beginning of 17th century. In younger individuals, a bicuspid valve is present in about 80% of the cases. The traditional cardiovascular risk-factors for ischemic heart disease have been linked to AS, and the histology of the stenotic aortic valve and the atherosclerotic plaques shares several features such as inflammation, lipid deposition and calcification. High levels of the lipoprotein Lp(a) has been linked to both atherosclerosis and AS, and a causal relation with AS is supported by Mandelian randomisation. End-stage renal disease is associated with increased risk of AS but if early impairment increases the risk is not known.

Material and methods: We identified 799 patients with surgery for valvular heart disease and/or disease of the ascending aorta with a prior participation in one of three large population based health surveys in northern Sweden (Västerbotten Intervention Program [VIP], MONItoring Of trends and Determinants in CArdivascular Disease survey [MONICA], and the Mammary Screening Project [MSP]). For each case, four referents matched by age, gender, type and date of survey, and geographical area were randomly selected. From the health surveys, data on cardiovascular risk-factors and health history as well as measurements of anthropometry, blood pressure, glucose and cholesterol levels were retrieved. Each case was carefully validated and data from pre- and perioperative assessments were collected. The presence of coronary artery disease (CAD) was determined from the preoperative coronary angiogram. Apolipoproteins B and A1, Lp(a), creatinine and cystatin C were analysed in samples obtained at the initial survey. As this is a matched case-referent study where cases and referents had the same follow-up duration within strata, logistic regression using the conditional maximum likelihood routine designed for matched analysis was used to estimate odds ratios (ORs) with 95% confidence intervals. Studied variables were tested in uni- and multivariable models.

Results: Paper 1: Of the identified 799 cases with questionnaires, 322 were primarily operated for AS, 91 for aortic regurgitation, 181 for mitral regurgitation, 131 for disease of ascending aorta, 52 for CAD (and for concomitant valvular or aortic disease). The remaining 22 had various indications for valvular heart surgery and were excluded. Altogether 38% of patients were women. Aortic stenosis: Hypertension (OR 1.87 [1.37–2.54]), diabetes (OR 1.78 [1.01–3.11]) and total cholesterol (OR 1.64 [1.07–2.49]) were associated with future AVR. After exclusion of concomitant CAD, none of the these risk-factors remained significant. Aortic regurgitation: None of the cardiovascular risk-factors was associated with increased risk for aortic regurgitation demanding surgery, whereas high levels of cholesterol were associated with reduced risk for surgery (OR 0.29 [0.12–0.71]). Mitral regurgitation: High levels of cholesterol associated with surgery for mitral regurgitation (OR 1.74 [1.01–3.00]), but not in those without CAD. Disease of the ascending aorta: Hypertension (OR 2.42 [1.44–4.06]) and previous smoking (OR 1.97 (1.12–3.49]) related to increased risk for surgery of the ascending aorta, whereas diabetes was inversely associated with surgery (OR 0.09 [0.01–0.73]). Excluding CAD, only diabetes remained protective (OR 0.24 [0.07–0.81]). Paper 2: 322 patients underwent AVR, and 70 had surgery before the age of 60 years and 252 had surgery after 60 years of age. After exclusion of patients with CAD, 49 and 82 patients remained in these age groups. Arterial hypertension associated with future AVR in those operated before the age of 60 years regardless of concomitant CAD or not (OR 3.40 [1.45–7.93] and OR 5.88 [1.46–23.72]). In those older than 60 years at surgery and with concomitant CAD, all traditional cardiovascular risk factors associated with surgery, but in those without concomitant CAD, only impaired fasting glucose (IFG) was associated with surgery (OR 3.22 [1.19–8.76]). Paper 3: 336 patients having surgery for AS. Lipoprotein(a) [Lp(a)] was independently associated with surgery in those with concomitant CAD (OR 1.29 [1.07–1.55]), but not in those without CAD. A high Apo B/A1 ratio was associated with surgery in patients with CAD (OR 1.43 [1.16–1.76]), but not in those without. Paper 4: The same cohort as in paper 3 was examined. Renal function was estimated by the ratio between glomerular filtration rates (eGFR) obtained from cystatin C and creatinine, and a low ratio indicates early impairment of renal function (“shrunken pore syndrome”). A high ratio independently associated with lower risk for future AVR (OR 0.84 [0.73–0.97]). Protective effect was seen in women but not in men (0.74 [0.60–0.92] and 0.93 [0.76 [0.76–1.13], respectively). After stratification for CAD, the association remained significant in women with CAD but not in men with CAD (0.60 [0.44–0.83] and 0.96 [0.76 [0.75–1.23], respectively).

Conclusion: The traditional cardiovascular risk-factors associated with future surgery for valvular heart disease and for surgery of the ascending aorta, however with a clear difference if there was concomitant CAD or not. Arterial hypertension was a major risk factor for surgery for AS in younger patients without CAD, whereas impaired fasting glucose (IFG) associated with surgery in elderly patients without CAD. High levels of Lp(a) and a high Apo B/A1 ratio were associated with future AVR only in patients with concomitant CAD. Similarly, early renal impairment expressed as low ratio of eGFR by cystatin C and by creatinine (“shrunken pore”) associated with future AVR.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2018. p. 63
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1941
Keywords
Valvular heart disease, aortic stenosis, bicuspid aortic valve, cardiovascular risk factors, hypertension, diabetes mellitus, smoking, hypercholesterolemia, obesity, shrunken pore, renal failure
National Category
Cardiac and Cardiovascular Systems
Research subject
Epidemiology; Cardiology
Identifiers
urn:nbn:se:umu:diva-144306 (URN)978-91-7601-825-5 (ISBN)
Public defence
2018-02-23, Sal B, NUS 1D-Tandläkarhögskolan, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2018-02-02 Created: 2018-01-31 Last updated: 2018-06-09Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3002-4877

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