| 1. |
- Ingelsson, Erik, 1975-
(författare)
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Insulin Resistance and Inflammation as Risk Factors for Congestive Heart Failure
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Congestive heart failure (CHF) is a major cause of morbidity and mortality and the identification of modifiable risk factors is crucial in order to diminish suffering of this common disease. The primary aim of this thesis was to investigate novel metabolic risk factors for CHF, with a focus on insulin resistance and inflammation. The secondary aim was to examine the validity of the CHF diagnosis in the Swedish hospital discharge register.This thesis was based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, a community-based prospective study started in 1970. The participants were examined at age 50 and 70 and the data was completed with annual updates on mortality and in-hospital morbidity using national registers. We showed that insulin resistance predicts CHF incidence independently of established risk factors in both middle-aged and elderly men. The previously described association between obesity and subsequent CHF may be mediated partly by insulin resistance. Moreover, it was established that inflammation, measured as erythrocyte sedimentation rate is a significant predictor of CHF, independent of established risk factors including an interim myocardial infarction. Furthermore, a low beta-carotene level, as well as an increased apolipoprotein B/A-I-ratio was found to predict CHF independently of established risk factors.We also showed that the validity of the CHF diagnosis in the Swedish hospital discharge register appears less precise than for other recently investigated cardiovascular diagnoses. However, when including only cases from selected clinics or cases with a primary diagnosis of CHF, the validity is comparable to the above diagnoses. In conclusion, insulin resistance and inflammation are strong independent risk factors for the development of CHF, and seem to be involved in the early process leading to CHF. If confirmed, our observations could have large clinical implications as they may offer new approaches in the prevention of CHF.
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| 2. |
- Vavruch, Camilla
(författare)
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Leptin and the Intersection of Cardiovascular Disease, Metabolism, and Adipose Tissue
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- According to the World Health Organization, cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, and it is the leading cause of death worldwide. The risk factors for CVD are divided into two major classes: non-modifiable (age, gender, family history) and modifiable (including tobacco use, type 2 diabetes mellitus (T2DM), physical inactivity, unhealthy diet, abdominal obesity, high cholesterol, dyslipidemia, and stress). Because CVD is a major cause of mortality and morbidity, new and clinically useful biomarkers of cardiovascular risk are of essence. Since obesity is a risk factor for CVD, new ways to achieve weight loss are also important. In this thesis, the focus is on leptin, a metabolic hormone with a pivotal function in the balance of appetite and satiety, and inducing weight loss. The adipose tissue releases leptin, with plasma levels of leptin reflecting the total adipose mass. Since it is related to both fat mass and cardiovascular risk, and is pro-inflammatory, it has been studied as a potential link between obesity, inflammation, hypertension, and vascular function. In paper I, we aimed to see if repeated cold exposure increased metabolic rate and/or brown adipose tissue (BAT) volume in humans. Out of 28 recruited participants, we allocated 16 to expose themselves to cold for one hour every day for six weeks, while 12 were controls, instructed to avoid cold exposure. Through magnetic resonance imaging, we found that supra-clavicular BAT volume had increased in an on-treatment analysis of the cold exposure group. In paper II, we used baseline data from 720 participants in “Cardiovascular Risk factors In Patients with Diabetes—a Prospective study in Primary care” (CARDIPP), all of whom had T2DM and were 55-66 years old at recruitment. We followed patients for incidence of ischemic heart disease (IHD) mortality and morbidity for 4-7 years, using the national Swedish Cause of Death and Hospitalization Registries. Our study showed that serum leptin levels related positively to the hazard ratio in both men and women, and predicted IHD independently of age, HbA1c, BMI, systolic blood pressure, and LDL/HDL-cholesterol ratio. This supports the use of serum leptin in patients with T2DM to add independent prognostic information in terms of IHD. When adding pulse wave velocity (PWV) and intima-media thickness to the model as markers of arterial stiffness, the finding of increased risk of IHD related to leptin levels remained statistically significant in men, but not in women. In paper III, we aimed to discover novel associations between leptin and circulating proteins, to possibly link leptin with the development of CVD in patients with T2DM. Using proximity extension assay, we investigated associations between 88 plasma proteins in the CARDIPP population. We replicated the associations passing the significance threshold in patients with T2DM in an independent cohort and found that adipocyte fatty acid binding protein (A-FABP) was significantly associated with leptin in both cohorts, more so in men than women. A-FABP can be found in white adipocytes and macrophages, and some studies have identified it as a circulating biomarker for metabolic syndrome, T2DM, and cardiovascular events. Finally, in paper IV, we analyzed data from 1 658 men and 1 678 women aged 50 to 65 when included in “The Swedish CardioPulmonary bioImage Study” (SCAPIS), focusing on leptin and its possible correlation with PWV. In bivariate correlations, we found log transformed leptin, and inflammatory markers IL-6, IL-18, and CRP, were all correlated in both men and women. In a multivariable linear regression, log transformed leptin correlated positively with PWV, independently of home blood pressure, smoking, non-HDL, BMI, T2DM, and IL-6, IL-18, and CRP. This suggests it may be possible to use leptin as a marker for PWV and arterial stiffness.In conclusion, this thesis provides new insights into leptin and its potential associations with other circulating proteins, and its connection to cardiovascular disease and inflammation, both in patients with T2DM and in healthy subjects. It also provides more insight into brown adipose tissue.
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| 3. |
- Hållmarker, Ulf, 1946-
(författare)
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Epidemiological Studies on Long Distance Cross-Country Skiers : Participants in the Vasaloppet 1955-2010
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to study the influence of physical activity on health. Risks and benefits of physical activity is of particular interest since there is a global trend of less physical activity among youths and adults.In order to investigate this aim we used a database from a large cross country ski race, Vasaloppet, with participants with a wide age range, and with both elite athletes and ordinary people who exercise and promote their health. The most serious risk of strenuous exercise is sudden death and it is challenging to identify preventive effects of major endemic diseases.Using epidemiological methodology we studied 200 000 Vasaloppet skiers and compared them with the general population. Based on personal identification numbers we added data from Swedish national personal and health registers, clinical registers as the cancer register, Swedeheart, or Swedish stroke register, and socioeconomic information from Statistics Sweden. In the Vasaloppet database we collected data on age, gender, finish time and number of races during the period 1989 to 2010.We evaluated risk of death during the race in two papers (I,II). During 90 years of annual races, cardiac arrest occurred in 20 skiers, of which five survived. The death rate is in average two per 100 000 skiers.We also studied the association with cancer incidence (paper III). The overall reduction of cancer was modest among skiers compared with the general population, but for cancers related to lifestyle the risks were markedly lower.We investigated the risk for recurrent myocardial infarction and found a 30% reduction among skiers (paper IV). In paper V we showed that skiers with a first stroke have a lower incidence of all-cause death. The skiers had a higher frequency of atrial fibrillation but had less severe stroke and no increased risk of recurrent stroke. Thus our data suggest that a lifestyle with a high level of physical activity may work as a protection after a cardiovascular event.Summary: The short excess mortality in endurance physical activity is by far outweighed by the long term protective effect of exercise in cardiovascular diseases and cancer.
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| 4. |
- Jobs, Elisabeth
(författare)
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Cathepsin S as a Biomarker of Low-grade Inflammation, Insulin Resistance, and Cardiometabolic Disease Risk
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cathepsin S is a protease important in major histocompatibility complex (MHC) class II antigen presentation and also in degrading the extracellular matrix. Studies, most of them experimental, have shown that cathepsin S is involved in different pathological conditions such as obesity, inflammation, atherosclerosis, diabetes, and cancer.The overall hypothesis of this report is that high levels of circulating cathepsin S, is a biomarker that reflects pathology induced by inflammation and obesity. The overall aim of this report was to investigate possible associations between circulating cathepsin S, inflammation, glucometabolic disturbance, and its associated diseases in the community. As cathepsin S appears to be a novel risk marker for several pathological conditions, we also wanted to examine the effect of dietary intervention on circulating cathepsin S concentrations.This thesis is based on data from three community-based cohorts, the Uppsala longitudinal study of adult men (ULSAM), the prospective investigation of the vasculature in Uppsala seniors (PIVUS), and a post-hoc study from the randomized controlled NORDIET trial.In the first study, we identified a cross-sectional positive association between serum cathepsin S and two markers of cytokine-mediated inflammation, CRP and IL-6. These associations were similar in non-obese individuals. In longitudinal analyses, higher cathepsin S at baseline was associated with higher CRP and IL-6 levels after six years of follow-up. In the second study, we identified a cross-sectional association between increased serum levels of cathepsin S and reduced insulin sensitivity. These associations were similar in non-obese individuals. No significant association was observed between cathepsin S and insulin secretion. In longitudinal analysis, higher cathepsin S levels were associated with an increased risk of developing diabetes during the six-year follow-up. In the third study, we found that higher serum levels of cathepsin S were associated with increased mortality risk. Moreover, in the ULSAM cohort, serum cathepsin S was independently associated with cause-specific mortality from cardiovascular disease and cancer. In the fourth study, we identified that adherence to an ad libitum healthy Nordic diet for 6 weeks slightly decreased the levels of plasma cathepsin S in normal or marginally overweight individuals, relative to the control group. Changes in circulating cathepsin S concentrations were correlated with changes in body weight, LDL-C, and total cholesterol.Conclusion: This thesis shows that circulating cathepsin S is a biomarker that independently reflects inflammation, insulin resistance, the risk of developing diabetes, and mortality risk. Furthermore, a Nordic diet moderately reduced cathepsin S levels in normal-weight and overweight men and women. This effect may be partially mediated by diet-induced weight loss and possibly by reduced LDL-C concentrations.
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| 5. |
- Nerpin, Elisabet, 1962-
(författare)
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The Kidney in Different Stages of the Cardiovascular Continuum
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum.The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death.This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress.In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease.Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.
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| 6. |
- Skau, Emma
(författare)
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Targeted multiplex proteomics for risk stratification in patients with cardiovascular disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Risk stratification is valuable in patients with cardiovascular disease (CVD). Proteins involved in different pathophysiological processes in atherosclerosis have shown prognostic capacity. A new technology, Proximity Extension Assay (PEA), enables the simultaneous analysis of numerous plasma proteins from a minimal amount of plasma. In this thesis, the overall aim was to identify and study prognostic protein biomarkers that could become useful in risk stratification. We used PEA to identify the biomarkers with the best prediction of long-term mortality among patients with acute myocardial infarction (AMI) and peripheral arterial disease (PAD). The study populations included consecutive patients with AMI from the Västmanland Myocardial Infarction Study (VaMIS), outpatients with carotid or lower extremity PAD from the Peripheral Arterial Disease Study in Västmanland (PADVa), and a population-based control cohort. A set of 92 proteins was analysed with PEA and related to follow-up data in the populations. The biomarkers which were best at predicting all-cause mortality were identified using LASSO regression analyses. The added value of the identified biomarkers to clinical risk markers was evaluated by logistic or Cox regression models. The associations between the plasma concentrations of growth differentiation factor 15 (GDF-15) to clinical risk factors, indicators of atherosclerotic burden, and variables of cardiac geometry and function were analysed with linear regression models. Spearman’s rank correlation coefficients compared the plasma concentrations obtained from conventional immunoassays and PEA for GDF-15 and N-terminal pro-brain natriuretic peptide (NT-proBNP) in the PAD population and the population-based cohort without PAD. The association between the two assay data and outcome was evaluated separately with Cox regression.GDF-15 and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) had the best prognostic performance for all-cause mortality among individuals with AMI, and PAD, and improved the risk prediction beyond the established risk markers.Circulating GDF-15 levels among individuals with PAD were independently associated with several of the clinical and biochemical risk variables, particularly diabetes and low low-density lipoprotein cholesterol.We demonstrated an excellent correlation and a similar prognostic performance of plasma levels of NT-proBNP and GDF-15 obtained by conventional assays compared with PEA in both cohorts. Except for high levels of NT-proBNP, the PEA reliably reflects the serum levels obtained from the conventional assay.Hopefully, our results can contribute to the finding of potential biomarkers useful in clinical practice in order to better identify subgroups among patients with CVD. In the long run, this might open up possibilities for individualised treatment and to more cost-effective follow-up routines, thus improving quality of life and longevity.
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| 7. |
- Stenemo, Markus
(författare)
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Molecular Epidemiology of Cardiovascular Disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiovascular disease is a major cause of morbidity and mortality, with increasing prevalence worldwide.Identification of risk markers may enable improved prevention by targeting high-risk individuals, earlier disease diagnosis and treatment, as well as stratification of disease subtypes with different treatment options, thereby minimizing side effects while increasing success rates.The overall aim of this thesis was to investigate associations between proteomic and metabolomic biomarkers, and the development of heart failure and ischemic stroke. Specific objectives were to examine potential causal pathways, and the added value in risk prediction of the identified risk markers.In Studies I–II, we performed proximity extension assay based proteomic profiling of ≥80 circulating proteins in the Swedish cohorts Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS n=901, median age 70), and the Uppsala Longitudinal Study of Adult Men (ULSAM, n=685, median age 77). In Study I, we identified nine proteins involved in apoptosis, inflammation, matrix remodeling, and fibrinolysis associated with incident heart failure, including growth differentiation factor-15 (GDF-15). In Study II, we identified several proteins associated with incident ischemic stroke, including GDF-15. Both studies revealed potential to improve disease risk prediction by using proteomic data.In Study III, we performed mass spectrometry-based metabolomic profiling in plasma or serum samples from PIVUS, ULSAM, and TwinGene (total n=3,924). The metabolites urobilin and sphingomyelin (30:1) were associated with incident heart failure.In Study IV, we followed up on the results of Studies I–II, performing Mendelian randomization analyses (a framework for causal analysis using genetic variants) in 1,053,527 individuals, with 88,448 coronary artery disease cases, 70,305 ischemic stroke cases, and 1,420 heart failure cases. This study supports a causal role of genetically elevated GDF-15 levels in heart failure development, but not in coronary artery disease or ischemic stroke.In conclusion, we identified multiple biomarkers associated with incident heart failure and ischemic stroke, potentially involved in early disease development. We also saw potential to improve disease risk prediction for incident heart failure and ischemic stroke using proteomics data.Our findings encourage further large-scale proteomic, metabolomic, and genetic studies to give new insights into heart failure and stroke pathogenesis.
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| 8. |
- Ärnlöv, Johan, 1970-
(författare)
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Left Ventricular Function in Elderly Men : Metabolic, Hormonal, Genetic and Prognostic Implications
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry.Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years.In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.
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